EXPERIMENTAL  RESEARCHES 

ON 

SPECIFIC    THERAPEUTICS 


UNIVERSITY 

OF 

&i£QR**& 


EXPE  RIMENTAL  RESEARCHES 


SPECIFIC  THERAPEUTICS 


BY 


PROF.  PAUL  EHRLICH,  M.D.,  D.Sc.OxoN. 
»« 

Director  of  the  Konigliches  Institut  fur  Experimentelle  Therapit, 
Frankfort. 


Ifcrlnris  for  1907 

OF 
THE    ROYAL    INSTITUTE    OF    PUBLIC    HEALTH 


PAUL    B.    HOEBER 

69     EAST     5QTH     STREET 

NEW   YORK 


Ess, 


[Printed  in  England], 


PREFACE. 


IT  was  with  very  sincere  pleasure  that  I 
accepted  the  invitation  of  the  Council  of  the 
Royal  Institute  of  Public  Health  with  which 
they  honored  me,  to  deliver  the  Harben  Lec- 
tures in  1907,  for  many  relationships  both  of  a 
scientific  and  social  character  have  always  con- 
tributed to  render  a  visit  to  England  one  of 
stimulus  and  recuperation. 

The  subjects  which  I  chose  for  my  lectures 
are  closely  related  with  those  questions,  with 
the  study  of  which  I  have  been  connected  during 
the  past  ten  years,  viz.,  the  theories  of  Immunity 
and  Atrepsy,  which  latter  is  connected  with  my 
researches  on  Cancer,  and  the  theory  of 
Chemico-therapeutics  which  I  have  enunciated 
in  connection  with  my  work  on  the  Trypano- 
somes. 

206460 


vi  PREFACE. 

I  am  publishing  these  lectures  with  a  feeling 
of  sincere  gratitude  for  the  kind  and  hospitable 
reception  which  I  received  in  London  from  my 
friends  and  colleagues,  and  especially  am  I 
anxious  to  express  my  indebtedness  to  Professor 
William  R.  Smith  for  all  his  kindness,  which 
rendered  my  visit  so  enjoyable.  I  would  also 
desire  to  thank  Dr.  Carl  Prausnitz  for  his  very 
valuable  help,  and  Professor  R.  Tanner  Hewlett 
for  kindly  revising  the  English  translation  of 
the  Lectures. 

P.  EHRLICH. 

FRANKFORT, 

April  22,  1908. 


EXPERIMENTAL   RESEARCHES   ON 
SPECIFIC   THERAPEUTICS. 


LECTURE   I. 

ON  IMMUNITY  WITH  ESPECIAL  REFERENCE  TO  THE  RELA- 
TIONS EXISTING  BETWEEN  THE  DISTRIBUTION  AND 
THE  ACTION  OF  ANTIGENS. 

THERE  can  be  no  doubt  that  the  three  great 
fields  of  knowledge,  Pharmacology,  Toxicology 
and  Therapeutics,  in  their  theoretical  and  prac- 
tical aspects  form  the  most  important  branches 
of  medicine.  It  is  matter,  therefore,  for  no 
surprise  that  in  the  study  of  the  various  sub- 
stances with  which  these  sciences  are  concerned, 
the  mode  of  action  and  the  reasons  for  such 
call  for  much  consideration,  and  theory  and 
speculation  necessarily  form  a  great  part  of  our 
study. 


2  EXPERIMENTAL  RESEARCHES 

Besides,  pharmacology  has  but  just  emerged 
from  the  stage  of  pure  observation  and  descrip- 
tion. One  was  content  formerly  with  describing 
the  physiological  effects  and  the  secondary  action 
of  substances  which  act  pharmaco-dynamically, 
as  well  as  the  morphological  changes  which 
they  bring  about  in  the  organs  and  tissues 
of  the  body.  Observations  made  on  an  em- 
pirical basis  such  as  this,  formed  a  mass  of 
most  needful  knowledge,  and  even  to-day  we 
have  no  hesitation  in  admitting  that  the  study 
of  the  symptomatology  of  drugs  is  still  a  work 
of  absolute  necessity  and  must  yield  very  fruitful 
results.  Indeed,  by  such  means  we  learn  not 
only  how  to  make  use  of  known  drugs  in  a 
purposeful  manner,  but  also  how  to  avoid  their 
undesired  secondary  actions.  But  merely  to 
increase  the  contents  of  our  pharmacopoeia  is 
not  to  add  to  our  resources  in  this  desirable 
direction :  for  such  an  increase  may  depend  on 
accidents,  which,  in  their  turn,  may  be  the 
outcome  of  empiricism.  It  is  to  the  great 
influence  which  chemistry  exerts  on  medical 
science  that  we  owe  the  change  in  this  state  of 
affairs ;  for  it  is  especially  necessary  to  have 
clear  ideas  of  the  relations  between  chemical 
constitution  and  pharmacological  action. 


ON  SPECIFIC  THERAPEUTICS.  3 

About  the  middle  of  the  last  century  the 
influence  of  these  inquiries-  made  itself  especi- 
ally felt,  and  this  influence  is  chiefly  evident  in 
the  mass  of  drugs  with  which  the  united  efforts 
of  synthetic  chemistry  and  pharmacology  have 
enriched  us.  But  observers  were  content  with 
an  advance  in  this  direction,  based  on  rational 
grounds.  They  recognised  a  limited  number  of 
atom-groupings,  which  were  of  importance  either 
for  their  therapeutic  or  their  toxic  action  ;  but 
the  drugs  used  were  directed  not  against  the 
causes  of  disease  but  against  the  symptoms  to 
which  these  gave  rise ;  it  was  not  the  causes  but 
their  effects  which  were  combatted.  Thera- 
peutics were  chiefly  symptomatic,  and  so  it  is  in 
many  cases  to-day.  Since  the  search  after  the 
seat  and  cause  of  disease  has,  from  the  time  of 
Morgagni,  and  especially  under  the  leadership 
of  Virchow's  genius,  influenced  our  entire  field 
of  thought,  the  effect  of  these  considerations  has 
become  more  evident  in  our  treatment.  The 
features  of  an  aetiological  treatment,  directed 
against  the  causes  and  the  seat  of  disease,  were 
not  satisfactorily  brought  out  by  merely  insisting 
on  the  relationship  which  existed  between  the 
constitution  of  drugs  and  their  action  ;  the  fact 
was  overlooked  that  between  chemical  consti- 

B  2 


4  EXPERIMENTAL  RESEARCHES 

tution  and  pharmacological  action  another  and 
important  bond  of  union  exists,  which  influences 
the  relations  between  the  pharmaco-dynamic 
agent  and  the  substance  on  which  it  is  intended 
to  act.  This  bond  of  union  is  the  mode  of 
distribution,  and  represents  the  sum  of  the 
peculiarities  of  the  cells  and  tissues  and  of  the 
drug.  In  this  we  have  to  do  with  a  principle 
so  obvious  that  it  should  at  once  be  accepted  as 
an  axiom,  but  even  when  accepted  as  an  axiom 
it  is  scarcely  ever  applied  to  the  study  of 
practical  questions.  The  reason  for  this,  I 
think,  lies  partly  in  a  certain  disinclination  to 
attempt  to  master  the  difficulties  of  the  problem, 
but  mainly  in  the  fact  that,  in  view  of  the 
triumphs  of  synthetic  chemistry,  per  se,  the 
biological  factor  of  the  pharmaco-dynamic 
action  is  somewhat  lost  sight  of.  I  may 
mention  that  from  the  beginning,  as  the  result 
of  my  studies  on  dyes,  I  have  endeavoured  to 
point  out  the  necessity  of  the  study  of  localisa- 
tion ;  in  a  word,  to  give  pharmacology  an 
aetiologically  therapeutic  tendency;  regarding 
the  details  of  this  I  shall  speak  further  in  my 
second  lecture.  Excepting  the  case  of  dyes, 
which,  by  reason  of  their  easily  appreciable 
properties  allow  their  distribution  in  the  organism 


ON  SPECIFIC  THERAPEUTICS.  5 

to  be  followed,  the  study  of  the  laws  which  govern 
distribution  is  exceedingly  difficult.  Besides, 
owing  to  the  great  number  of  chemicals  at  our 
disposal,  a  large  amount  of  empirical  work  must 
be  carried  out  before  we  are  able  to  find  those 
substances  which  in  any  given  case  will  give  the 
desired  mode  of  distribution.  All  the  greater, 
then,  must  be  our  admiration  for  the  powers  of 
nature,  in  view  of  the  fact  that  the  living 
organism,  when  it  takes  upon  itself  the  pro- 
duction of  curative  agents,  does  this  in  such  a 
manner  as  to  form  ideal  aetiological  remedies. 
The  protective  substances  of  the  blood,  with 
which  this  lecture  is  concerned,  completely  fulfil 
the  requirements  of  the  case,  and  the  study  of 
antigens  and  antibodies  may  form  the  basis  of  the 
relationships  which  must  exist  between  con- 
stitution, distribution,  and  action,  in  order  that 
our  treatment  may  be  successful. 

Since  the  conditions  of  substances  treated  of 
in  the  study  of  immunity  are  specially  clear  and 
matters  of  common  knowledge,  I  shall  begin  the 
discussion  of  my  views  regarding  distribution 
and  localisation  with  the  consideration  of  this 
class  of  phenomena  of  pharmaco-dynamic  and 
toxicological  action. 

The  discovery  of  antitoxins  by  von  Behring, 


6  EXPERIMENTAL  RESEARCHES 

fundamental  in  itself,  has  opened  to  pharmaco- 
logy and  therapeutics  this  new  field  in  which  the 
principle  of  distribution  is  exemplified  in  an 
ideal  manner  :  for  antitoxins  and  antibacterial 
substances  are,  so  to  speak,  charmed  bullets 
which  strike  only  those  objects  for  whose 
destruction  they  have  been  produced  by  the 
organism.  I  call  these  substances  monotropic  ; 
the  monotropism  of  these  antibodies  is  charac- 
terised by  the  fact  that  they  are  bacteriotropic  or 
generally  speaking  aetiotropic,  i.e.,  they  are  di- 
rected against  bacteria  or  against  those  products 
of  their  metabolism  (toxins)  which  cause  disease. 
The  definition  of  monotropism  is,  therefore,  here 
overlapped  by  that  of  specificity,  which,  in  the 
language  of  the  study  of  immunity,  is  the  cha- 
racteristic of  monotropic  action.  As  the  cause 
of  this  specificity  we  must  note,  in  my  opinion, 
only  the  effect  of  chemical  relations  which  exist 
between  the  agents  of  infection,  or  their  products, 
and  the  antibodies.  From  the  very  beginning 
my  standpoint  has  been,  that  all  those  sub- 
stances which  have  the  power  to  bring  about 
the  creation  of  antibodies,  I  mean  the  antigens, 
must  be  distinguished,  as  a  matter  of  princi- 
ple, from  the  other  pharmaco-dynamical  and 
poisonous  substances.  That  distinction  I  con- 


ON  SPECIFIC  THERAPEUTICS.  7 

sider  to  be  of  the  greatest  importance,  and  this 
is  further  borne  out  by  the  fact  that  in  spite  of 
the  most  strenuous  endeavours  we  have  been 
unable  to  find  any  antigen  of  a  known  chemical 
constitution. 

I  believe  that  the  absorption  of  antigen-like 
substances  by  the  body  is  a  phenomenon 
which  bears  a  close  resemblance  to  the  assimi- 
lation of  nutritive  substances.  In  the  case  of 
the  other  poisonous  substances  we  find  more 
simple  phenomena  as  causes  of  localisation,  but, 
in  my  opinion,  the  powers  which  influence  the 
distribution  of  toxins  and  kindred  substances, 
belong  to  the  domain  of  chemical  synthesis. 
There  has  been  a  tendency  of  late  to  bring  the 
colloid  nature  of  immune  substances  into  the 
foreground,  and  thus  the  impression  is  conveyed 
that  the  whole  subject  of  these  phenomena 
might  be  explained  on  the  ground  of  the  sub- 
stances being  colloid.  Against  this  view  it 
seems  to  me  to  be  necessary  to  insist  upon  the 
fact  that  colloid  nature  and  chemical  reactive 
power  do  not  exclude  one  another ;  for  colloids 
possess,  just  as  other  substances  do,  certain 
groupings  of  atoms  which  render  them  capable 
of  reactions  of  a  synthetic  nature.  Thus,  one 
may  introduce  into  certain  aromatic  nuclei  of 


8  EXPERIMENTAL  RESEARCHES 

the  protein  molecule  chemical  atom-groups,  e.g., 
the  nitro-,  the  amido-,  etc.,  or,  on  the  other 
hand,  the  reactive  power  of  any  such  groups  as 
may  be  present  can  be  inhibited,  as  by  the 
removal  of  the  amid.  I  would  here  remind  you 
of  the  researches  of  Obermayer  and  Pick,  which 
show  that  by  purely  chemical  substitution  of 
this  kind  one  may  also  profoundly  alter  the 
antigenic  character  of  albuminous  substances, 
so  that  in  place  of  specificity  for  a  kind 
("  Artspecifitat  ")  we  have  a  specificity  of 
chemical  constitution.  I  would  remind  you 
also  of  the  behaviour  of  certain  colloid  dyes — 
for  example,  chromazon-red,  which  possesses  all 
the  properties  of  the  azo-dyes,  but  differs  from 
them  in  possessing  an  aldehyde  group ;  it  is 
thus  able  to  react  with  hydrazin,  and  by  union 
therewith  to  be  transformed  into  a  hydrazon  of 
blue  colour.  Besides,  I  do  not  believe  that  for 
the  explanation  of  such  reactions,  especially  of 
their  specific  nature,  a  few  analogies  drawn  from 
certain  phenomena  of  the  hitherto  obscure  chem- 
istry of  colloids  are  sufficient  ;  and  as  a  matter 
of  fact  it  seems  to  me  that  the  ever-increasing 
endeavour  to  build  causal  relationships  on  the 
ground  of  purely  formal  analogies,  is  but  little 
fitted  to  advance  our  knowledge.  The  condi- 


ON  SPECIFIC  THERAPEUTICS.  9 

tion  therefore  necessary  for  such  action  is  the 
presence  of  two  groups,  whose  chemical  rela- 
tionship is  of  the  closest,  and  whose  interaction 
is  therefore  the  condition  of  their  union.  This 
axiom  as  to  union  is  the  basis  of  my  side-chain 
theory. 

Let  us  consider  in  the  first  place  the  action  of 
comparatively  simple  toxins,  which  differ  in  the 
phenomena  of  intoxication  to  which  they  give 
rise ;  the  action  of  the  diphtheria-toxin,  for 
example,  is  absolutely  different  from  that  of  the 
tetanus-toxin.  In  the  case  of  toxins,  too,  we  are 
justified  in  assuming  a  connection  between  their 
chemical  constitution  and  action,  just  as  in  the 
case  of  poisons  of  known  chemical  constitution  ; 
this  connection  can  in  many  cases  be  proved. 
As  an  instance  of  this  latter  I  would  note  the 
fact  that  in  the  cocaine  series  it  is  the  residue 
of  benzoyl  which  causes  their  anaesthesiophoric 
character ;  that  the  soporific  action  of  certain 
disulphons  is  entirely  due  to  the  presence  in 
them  of  ethyl  groups ;  and  that  the  dulcific 
character  of  certain  sweet  substances,  e.g., 
phenetidin-urea,  is  due  to  a  like  group.  In  the 
case  of  the  toxins  there  is  a  difficulty  in  our 
way,  due  to  the  fact  that,  up  till  now,  they  have 
not  lent  themselves  to  chemical  analysis  ;  but 


10    EXPERIMENTAL  RESEARCHES 

in  their  case,  too,  it  has  been  found  to  be  a 
fruitful  heuristic  principle  to  formulate  for  them 
similar  relations  between  their  constitution  and 
their  action.  Thus  I  designate  that  group  of 
the  toxin  molecule  which  is  the  cause  of  its 
peculiar  poisonous  action  as  its  toxophoric 
group ;  but  the  presence  of  this  toxophoric 
group  is  not  of  itself  sufficient  to  bring  about 
the  poisonous  action — for  whilst  the  guinea-pig 
is  exceedingly  sensitive  to  the  tetanus  toxin, 
the  rabbit  possesses  a  relative  immunity.  The 
cause  of  such  difference  we  must  therefore 
attribute  to  the  distribution  or  localisation  of 
the  toxin. 

When  the  poison  and  the  organs  sensitive  to 
it  do  not  come  in  contact,  or  when  sensitiveness 
of  the  organs  does  not  exist,  the  action  remains 
absent. 

If  we  assume  those  peculiarities  of  the  toxins 
which  cause  their  distribution  to  be  localised  in 
a  special  group  of  the  toxin  molecule,  and  the 
power  of  the  organs  and  tissues  to  react  with 
the  toxin  to  be  localised  in  special  atom  groups 
of  the  protoplasm,  we  arrive  at  the  basis  of  my 
side-chain  theory.  The  distributive  group  of 
the  toxins  I  call  the  "  haptophoric  group,"  and 
the  corresponding  chemical  organs  of  the  proto- 


ON  SPECIFIC  THERAPEUTICS.  11 

plasm  the  "  receptors."  The  relations  between 
the  receptors  and  the  haptophoric  groups  repre- 
sent the  conditions  under  which  distribution  takes 
place.  The  toxic  action  can  occur  only  when 
receptors  fitted  to  anchor  the  toxins  are  present. 

The  existence  of  receptors  can  be  proved 
experimentally.  For,  if  to  a  solution  of  toxin 
there  be  added  receptors  suitable  for  anchoring 
the  toxin,  the  solution  becomes  non-poisonous ; 
this  "  binding  experiment"  plays  a  great  part 
in  the  study  of  immunity,  since  Wassermann, 
working  on  the  basis  of  the  conclusions  to  be 
drawn  from  the  side-chain  theory,  first  showed 
that  those  cells  of  the  central  nervous  system, 
which  were  known  to  be  affected  by  the  action 
of  tetanus-toxin,  anchored  the  toxin. 

In  order  that  the  poisonous  action  may  take 
place,  we  must  presume  not  only  the  presence 
of  receptors,  but  that  they  should  be  present  in 
positions  favourable  to  the  toxin  action  being 
brought  about.  When  both  the  receptors  and 
the  organs  sensitive  to  the  action  of  the  poison 
are  present,  the  conditions  for  infection  are 
naturally  most  favourable ;  then  distribution 
takes  place  at  once,  the  poison  circulating  until 
it  reaches  the  sensitive  cell.  The  action  of  the 
tetanus-toxin,  in  the  case  of  the  guinea-pig,  is 


12          EXPERIMENTAL  RESEARCHES 

monotropic,  for  receptors  for  the  tetanus  spasmin 
are  present  only  in  the  central  nervous  system  ; 
on  the  other  hand,  in  the  rabbit,  suitable 
receptors  are  present  not  only  in  the  central 
nervous  system,  but  also  in  other  organs  and 
in  the  connective  tissue,  and  the  type  of  distri- 
bution in  this  animal  is  more  complex,  and 
depends  upon  the  point  of  entrance  of  the 
infection  or  injection.  Thus  the  varying  sensi- 
tiveness of  different  species  to  the  same  toxin 
may  be  explained.  The  localisation  of  the 
receptors  is,  then,  of  great  moment  for  the 
distribution  of  toxin  in  the  organism,  and  con- 
sequently for  its  sensitiveness  to  poisonous 
action.  One  may  therefore,  in  general,  dis- 
tinguish four  different  types  of  distribution  : 

(1)  In  which  fitting  receptors  are  not  present, 
the   animal   possessing   natural   immunity  (the 
formation  of  antibodies  cannot  take  place). 

(2)  In  which  receptors  are  present,  but  only 
in  those  organs  on  which  the  poison  does  not 
act,  or  in   organs  of  lesser  importance ;    here, 
again,  the  animal  possesses  natural   immunity 
(antibodies  may  be  formed,  and  immunisation 
is  easily  carried  out). 

(3)  In   which   the   receptors    are   distributed 
over   various   parts   of  the   organism,   and   are 


ON  SPECIFIC  THERAPEUTICS.  13 

present  in  the  organs  which  are  sensitive  to  the 
action  of  the  poison.  Here  a  relative  immunity 
exists,  and  the  possibility  of  infection  depends 
chiefly  upon  the  manner  in  which  the  poison  is 
introduced  (the  conditions  for  antibody  forma- 
tion are  present,  and  those  for  immunisation 
are  more  or  less  favourable). 

(4)  In  which  the  receptors  are  present  only 
in  the  organs  which  are  sensitive  to  the  poison  ; 
in  this  case  the  organism  is  exceedingly  sensitive 
to  the  poison  (antibody  formation  is  possible  ; 
but  immunisation  is  difficult  to  carry  out,  and 
must  be  begun  with  small  doses,  or  with 
weakened  poisons). 

I  think  that  this  systematic  division  clearly 
shows  the  possibilities  of  distribution  and 
localisation,  as  well  as  the  conditions  under 
which  a  poisonous  action  can  take  place,  and 
what  must  be  the  aim  of  antitoxic  treatment, 
viz.,  the  alteration  of  the  natural  conditions  of 
distribution  and  the  interference  with  the  action 
of  the  poison. 

In  my  view,  which  is  based  on  extensive 
experience  in  experimental  research,  the  anti- 
toxins are  purely  and  simply  receptors  fitted  for 
union  with  the  poisons  which  have  entered  the 
circulation.  When,  for  therapeutic  or  prophy- 


14     EXPERIMENTAL  RESEARCHES 

lactic  purposes  we  inject  an  antitoxic  serum, 
the  number  of  receptors  in  the  organism  fitted 
for  union  with  the  poison  is  increased,  the 
quantity  of  receptors  introduced  being  charac- 
terised by  the  fact  that,  as  antitoxins,  they 
represent  dissolved  cell  contituents,  which,  by 
their  union  with  the  toxin,  can  do  no  harm,  but 
by  their  presence  in  considerable  quantity  bring 
about  a  marked  change  in  the  conditions  of 
distribution  in  the  organism.  The  receptors  of 
the  organs  which  are  sensitive  to  the  action 
of  the  poison  are  reinforced  by  a  large  number 
of  free  antitoxin  receptors,  which,  by  reason  of 
the  factor  of  distribution,  and  also  because  they 
take  up  the  toxin  in  the  juices  of  the  organism, 
bring  about  this  condition  of  affairs.  The  toxin 
is  thus  either  kept  away  from  the  organs  which 
it  threatens  to  attack,  or  it  comes  in  contact 
with  them  only  in  an  inconsiderable  amount, 
and  so  the  disease  runs  a  favourable  course. 
Of  course  the  toxin,  which  has  already  become 
united  to  the  cell,  and  has  exerted  a  deleterious 
influence  upon  it,  cannot  be  rendered  innocuous  ; 
for  we  know  that  in  all  reactions  of  a  similar 
nature  observed  in  the  study  of  immunity, 
primary  union  is  followed  by  a  stage  of 
secondary  consolidation,  a  stage  in  which,  even 


ON  SPECIFIC  THERAPEUTICS.  15 

by  the  addition  of  a  large  number  of  receptors 
of  the  needed  description,  we  cannot  release 
the  toxin  from  the  union.  We  see,  then,  the 
limitations  of  antitoxic  treatment,  which  is,  in 
the  true  sense  of  the  term,  a  distributive  treat- 
ment ;  the  antitoxins  are  really  specific  drugs 
by  using  which  we  run  no  risk  of  harming  the 
component  parts  of  the  organism,  but  which, 
thanks  to  their  specific  monotropism,  influence 
the  toxic  agent  alone.  The  relations  which  exist 
between  constitution  and  action  are  therefore  in 
no  sense  influenced  by  the  action  of  the  anti- 
toxins. The  toxin  molecule,  which  is  anchored 
by  the  antitoxin,  still  possesses  a  toxophoric 
group,  which,  if  it  could  but  obtain  a  suitable 
localisation,  would  immediately  develop  its 
characteristic  action. 

I  have  always  held  the  view  that  the  anti- 
toxins do  not  in  any  way  destroy  the  toxin,  but 
that  they  merely  limit  its  sphere  of  action  by 
combining  with  it.  If  further  proof  of  the 
correctness  of  this  view  be  required,  we  have  it 
in  the  researches  carried  out  by  Morgenroth, 
who  showed  that  in  suitable  cases  the  toxin 
may  be  entirely  regained  from  a  perfectly  neu- 
tral union  of  toxin  and  antitoxin,  just  as  glu- 
cosides  may  by  suitable  treatment  be  resolved 


16  EXPERIMENTAL  RESEARCHES 

into  their  two  components.  The  antitoxin, 
then,  exercises  its  curative  influence  merely  by 
anchoring  the  distributive  group  of  the  toxins. 

When  we  speak  of  monotropism  or  specificity 
in  the  case  of  antigens  and  antibodies,  we  of 
course  mean  only  the  chemical  relations  between 
haptophoric  groups  and  receptors.  For  example, 
toxins  may  be  specific  and  yet  act  upon  the  cells 
of  all  species  of  animals,  if  the  toxin-anchoring 
receptors  be  widespread  amongst  them.  The 
other  extreme  we  find  in  those  cases  in  which 
the  organism  itself  reacts  to  elements  intro- 
duced into  it  and  forms  substances,  antibodies, 
which  act  on  the  corresponding  antigens  ;  we 
are  here  dealing  with  antibodies  which  are 
specifically  monotropic,  just  as  the  antitoxins 
are,  and  which  affect  only  those  substances  to 
which  they  owe  their  origin.  The  only  difference 
is  that  the  antitoxins  act  by  localisation  alone — 
when  they  have  anchored  the  toxins  their  work 
is  done.  The  other  antibodies,  it  is  true,  act  at 
first  in  a  similar  way  on  the  substances  sensitive 
to  them  ;  but  they  have  a  further  action  on  the 
anchored  substances,  an  action  which  is  either 
direct,  as  in  those  cases  (agglutinins  and  pre- 
cipitins)  in  which,  like  the  toxins,  they  have 
special  ergophoric  groups,  or  indirect,  in  that 


ON  SPECIFIC  THERAPEUTICS.  17 

the  union  is  merely  a  preliminary  to  their  further 
action  on  their  prey.  Thus  one  class  of  these 
antibodies  has  the  power  of  rendering  the  cells 
assimilable  by  phagocytes  (opsonins,  bacterio- 
tropic  substances) ;  another  class  (amboceptors) 
has  the  power  of  rendering  the  cells  liable  to 
the  action  of  toxin-like  constituents  of  the  blood 
serum  (complements).  In  the  latter  case  by 
the  simultaneous  action  of  two  substances  a 
destructive  effect  is  produced.  These  sub- 
stances are  also  called  cytotoxins.  For  the 
study  of  these  the  way  has  been  prepared  by 
the  work  of  Pfeiffer,  Metchnikoff,  and  Bordet, 
and  by  the  discovery  of  Metchnikoff  and 
Bordet  that  haemolysins  are  produced  by  im- 
munisation against  blood  corpuscles. 

These  haemolysins  are  of  special  importance  in 
considering  the  question  of  the  relations  between 
constitution,  distribution,  and  action,  because, 
in  their  case,  the  haptophoric  and  toxophoric 
groups  are  distinct,  distribution  and  toxic 
effect  being  dependent  upon  two  different  sub- 
stances, the  more  stable  amboceptor  controlling 
the  distribution,  and  the  labile  complement 
the  toxic  effect.  The  complement  has  no 
direct  relations  with  the  cell,  on  which  it  acts 
only  through  the  medium  of  the  amboceptor, 

c 


18  EXPERIMENTAL  RESEARCHES 

It  is  a  normal  constituent  of  the  blood-serum, 
and  its  quantity  undergoes  no  change  as  a  re- 
sult of  the  process  of  immunisation.  On  the 
other  hand  the  amboceptor  is  a  new  formation 
brought  about  by  immunisation,  and,  on  the 
ground  of  the  principle  already  admitted,  it 
must  appear  probable  that  the  amboceptor,  like 
the  antitoxins,  possesses  a  marked  monotropism 
for  the  corresponding  antigen.  It  was  there- 
fore not  the  result  of  accident,  but  of  logical 
sequence,  that  my  first  researches,  carried  out 
with  Morgenroth,  on  the  mechanism  of  haemo- 
lysis led  us  to  the  fundamental  conclusion 
that  the  amboceptor  alone  stands  in  direct 
relation  to  the  cell,  and  is  quantitatively 
anchored  by  it.  This  anchoring  of  the  ambo- 
ceptor takes  place  with  a  maximum  of  chemical 
energy — it  occurs  even  at  o°  C. 

The  union  of  the  amboceptor  and  the  cell  has 
no  harmful  results  on  the  latter.  On  the  other 
hand,  the  amboceptor-laden  cell  is  exposed  to 
the  action  of  the  complement,  which  by  itself  is 
harmless.  As  regards  complements,  what  I 
have  said  about  toxins  holds  true ;  they  may  be 
regarded  as  toxin-like  substances  which  possess 
a  haptophoric  group,  and  a  toxophoric  group 
which  I  call  the  "  zymotoxic "  group.  That 


ON  SPECIFIC  THERAPEUTICS.  19 

these  groups  are  independent  of  each  other,  is 
well  seen  in  the  case  of  modified  complement— 
"complementoid,"  as  numerous  test-tube  experi- 
ments have  proved.  Of  special  interest  are  the 
conditions  of  their  distribution.  The  real  state 
of  affairs,  which  has  been  thoroughly  investi- 
gated, especially  in  the  case  of  haemolysins,  is 
this :  the  intact  erythrocytes  do  not  unite  with 
the  complement,  which,  however,  is  anchored 
by  the  complex  of  erythrocyte  and  ambo- 
ceptor.  A  closer  acquaintance  with  the  condi- 
tions which  govern  distribution  in  this  matter, 
cannot  be  arrived  at  by  the  hypothesis  that 
the  erythrocyte  is  sensitised  by  the  amboceptor 
in  such  manner  that  an  action  of  the  com- 
plement is  rendered  possible.  If  one  accepts 
the  theory  of  Bordet,  which  really  consists  of 
the  denial  of  the  existence  of  direct  relations 
between  amboceptor  and  complement,  one  enters 
the  realm  of  pure  speculation ;  for  one  must 
then  presume  new  affinities  between  the  ery- 
throcyte and  complement  to  arise  under  the  in- 
fluence of  the  amboceptor.  For  this  assump- 
tion we  have  no  grounds.  Bordet's  method  of 
proof  must,  therefore,  limit  itself  to  indirect 
conclusions,  and  consists  merely  of  objections 
to  the  view  held  by  Morgenroth  and  myself, 

c  2 


20  EXPERIMENTAL  RESEARCHES 

that  the  amboceptor  and  the  complement  stand 
in  direct  relationship  to  one  another.  As  a 
matter  of  fact,  from  all  sides  proofs  of  the 
existence  of  this  direct  relationship  have  been 
advanced,  and  I  think  that  the  great  majority 
of  my  colleagues  to-day  accept  my  view,  which 
is  known  as  the  amboceptor  theory.  It  is 
true,  as  we  have  from  the  beginning  insisted, 
that  the  distributive  relation  of  the  complement 
in  the  presence  of  the  amboceptor  is  not  that  of 
maximum  chemical  affinity  ;  indeed,  we  have, 
on  the  contrary,  as  a  rule  an  exceedingly  loose 
relationship  which  perhaps  corresponds  to  a 
reversible  reaction.  To  show  that  this  relation 
is  purposeful,  we  need  only  the  following  proof 
— amboceptors  are  already  present  in  large 
quantity  and  of  various  kinds  in  the  blood- 
serum  of  normal  animals.  What,  then,  would 
happen  if  the  entire  mass  of  normal  ambo- 
ceptors reacted  with  pronounced  avidity  with 
the  complement  ?  Obviously  the  entire  mass 
of  complement  would  be  anchored  by  the  com- 
plementophile  groups  of  the  amboceptors,  and 
there  would  be  no  free  complement  present  in 
the  living  body.  The  grave  results  of  such  a 
state  of  affairs  are  evident ;  as  soon  as  the 
necessity  for  the  action  of  complements  with  a 


ON  SPECIFIC  THERAPEUTICS.  21 

special  kind  of  amboceptor  arose,  there  would  be 
no  complement  available,  all  having  previously 
been  used  up  for  the  action  of  indifferent  ambo- 
ceptors.  It  is  thus  owing  to  the  fact  that  the 
complement  is  free  or  only  loosely  united  to  the 
amboceptors  in  the  circulation,  that  at  a  given 
moment  it  is  ready  for  use.  The  maximum 
stimulus  to  action  is  rendered  possible  by  the 
anchoring  of  the  amboceptor  to  the  erythrocyte, 
the  avidity  of  the  former  toward  the  complement 
being  thus  increased.  This  increase  of  avidity 
which  consists  in  the  chemical  affinity  of  the 
complementophile  group  for  the  complement 
being  carried  to  its  maximum,  represents  the 
gist  of  our  knowledge  of  the  action  of  the 
amboceptor. 

The  amboceptor,  therefore,  exercises  the 
important  function  of  bringing  about  a  specific 
modification  of  those  conditions  existing  in  the 
organism  which  determine  the  distribution  of 
complements,  and  which  otherwise  are  not  very 
evident.  It  causes  the  complements  to  become 
monotropic  by  its  union  with  the  given  sub- 
stance. The  complements  are  thus  localised 
by  amboceptors  which  have  previously  become 
united  to  the  substance — cell  or  otherwise.  At 
the  same  time  this  action  represents  a  purposive 


22  EXPERIMENTAL  RESEARCHES 

saving ;  if  the  complement  were  already  a  con- 
stituent part  of  the  amboceptor,  then — as  the 
complement  is  easily  destroyed — there  would 
often  be  no  action.  The  purposive  saving  is 
evident  from  the  fact  that  only  in  case  of  need 
the  amboceptor  becomes  able  to  combine  with 
the  complement,  and  from  the  fact  that  com- 
plementoids  which,  by  reason  of  having  lost  the 
zymotoxic  group,  become  incapable  of  action, 
have  at  the  same  time  lost  some  of  their  avidity 
for  the  amboceptor.  By  this  change  in  the  dis- 
tributive quality  of  the  complement  that  is 
associated  with  the  formation  of  complementoid, 
the  sphere  of  action  of  the  amboceptor  is  con- 
siderably extended.  Of  other  possible  influences 
which  may  govern  distribution  and  action  we 
have  an  indication  given  by  the  work  of  Ferrata. 
Under  Morgenroth's  direction  he  carried  out  a 
research,  from  which  it  appears  that  a  comple- 
ment is  not  a  single  body,  one  and  indivisible ; 
for  in  a  salt-free  medium  it  is  split  up  into  two 
components,  which  are  capable  of  action  only 
when  they  work  in  concert  in  a  salt  solution. 
As  to  the  intimate  relations  of  these  two  com- 
ponents, the  researches  which  were  carried  out 
at  the  suggestion  of  Sachs  by  Dr.  Brand  appear 
to  indicate  that  in  the  blood  serum  they  are 
always  united. 


ON  SPECIFIC  THERAPEUTICS.  23 

The  increase  of  avidity,  which  forms  the 
basis  of  the  mode  of  action  of  the  amboceptor, 
not  only  governs  the  phenomena  which  occur  in 
the  organism,  but,  since  it  lends  itself  to  test- 
tube  experiments,  also  opens  up  a  wide  field  for 
serum  diagnosis.  If  we  remember  that  the 
amboceptors,  by  their  union  with  the  sensitive 
substances — cells  or  dissolved  bodies — exert 
such  a  marked  localising  influence  on  the 
complements,  it  is  evident  that  in  a  mixture 
of  an  amboceptor  and  its  corresponding  antigen, 
if  the  presence  of  the  one  constituent  of  the 
mixture  be  known,  that  of  the  other  can  be 
proved  by  the  occurrence  of  the  phenomenon  of 
complement-fixation. 

This  method,  which  was  elaborated  by  Neisser 
and  Sachs  on  the  basis  of  the  work  of  Bordet, 
Gengou  and  Moreschi,  for  the  medico-legal 
test  of  the  source  of  blood  by  "  complement 
deviation/'  depends  solely  on  the  principle  of 
this  increase  of  avidity.  And,  thanks  to  the 
genius  of  Wassermann,  we  possess  a  similar 
method  of  sero-diagnosis  for  some  infectious 
diseases,  the  cause  of  which  is  at  present 
unknown  or  invisible — a  method  which  has 
yielded  valuable  results  and  gives  great  promise 
for  the  future. 


24  EXPERIMENTAL  RESEARCHES 

In  practice,  too,  we  have  a  further  advantage 
in  the  fact  that  the  increase  of  avidity  affects 
not  one  complement  alone,  but,  as  a  rule,  all  the 
complements  circulating  in  the  blood.  For  the 
complement-deviation  test  we  may  then  choose 
at  will  a  complement  which  exercises  any  special 
function,  and,  merely  on  practical  grounds,  we 
choose  hsemolytic  complements.  The  peculiar 
power  of  the  amboceptor  to  fix  a  large  number 
of  complements,  is  not  to  be  wondered  at 
in  view  of  the  biological  function  of  the  ambo- 
ceptor. This  I  hold  to  be,  under  physiological 
conditions,  that  of  seizing  upon  and  elaborating 
nutritive  substances.  By  its  cytophile  group 
the  amboceptor  is  enabled  to  combine  with 
substances  of  the  most  varied  kinds,  provided 
that  they  possess  fitting  receptors.  We  have, 
then,  merely  an  increase  of  purposive  function 
in  the  fact  that  the  amboceptor  is  furnished 
with  a  host  of  complementophile  groups  which 
enable  the  most  varied  kinds  of  complement  to 
act — it  may  be  simultaneously.  This  is  the 
consequence  of  the  multiceptive  nature  of  the 
amboceptor. 

As  regards  increase  of  avidity,  the  fact  that 
the  anchoring  of  the  amboceptor  to  the  cell 
causes  the  avidity  for  the  complement  to  be 


ON  SPECIFIC  THERAPEUTICS.  25 

increased,  in  no  way  precludes  an  increase  of 
the  avidity  of  the  amboceptor  for  the  cell  taking 
place  in  consequence  of  the  anchoring  of  the 
complement.  Besides  a  few  normal  amboceptors 
of  the  blood-serum  in  which  this  is  observed, 
we  find  that  it  occurs  in  a  marked  degree  in  the 
case  of  those  poisons  which  act  by  the  united 
action  of  two  components,  the  part  of  the  comple- 
ment being  played  by  lecithin.  Thus,  the  power 
of  forming  lecithids  has  been  studied  by  Kyes, 
who  proved  its  existence  in  the  case  of  snake 
and  scorpion  poisons,  and  by  Morgenroth  and 
Carpi,  who  studied  bee  poison.  The  action  of  the 
venom  in  these  cases  corresponds  to  that  of  an 
amboceptor,  and  the  conditions  for  more  careful 
analysis  are  very  favourable  ;  for  snake  poison 
and  lecithin  are  both  stable  substances,  and  the 
latter  belongs  to  a  class  whose  chemical  com- 
position is  known.  Thus  Kyes  was  enabled  to 
isolate  and  analyse  the  substance  produced  by 
the  reaction  of  snake  poison  with  lecithin. 
Cobra-lecithid  was  found  to  be  a  mono-stearyl 
lecithin,  and  represents  the  result  of  a  typical 
series  of  processes  which  certainly  take  place  in 
cell  life  and  in  many  phases  of  immunity.  These 
processes  occur  in  consequence  of  the  union 
of  albuminous  substances,  possessing  special 


28  EXPERIMENTAL  RESEARCHES 

actions,  with  lecithin  or  other  fatty  substances, 
the  resulting  compound  showing  special  charac- 
teristics. Thus,  cobra-lecithid  is,  like  cobra 
poison,  soluble  in  water,  and  like  lecithin, 
soluble  in  fat  solvents;  in  its  physical  properties, 
therefore,  it  is  a  link  between  albumins  and 
lipoid  substances,  and  is  therefore  especially 
suited  for  distribution. 

It  is  a  special  characteristic  of  the  formation 
of  lecithids  that  out  of  two  absolutely  non- 
poisonous  substances  a  powerful  poison  is 
formed,  which,  in  its  biological  and  physico- 
chemical  reactions,  differs  markedly  from  the 
two  substances  from  which  it  sprang,  and  does 
not  contain  lecithin  as  such,  one  fatty-acid 
residue  being  removed  during  the  process  of 
formation.  I  believe  that  this  possibility  of  the 
transformation  of  certain  substances,  inactive 
in  themselves,  from  albuminoids  to  lipoids  of 
powerful  action — a  transformation  which  has 
been  proved  to  occur  in  the  case  of  snake 
poisons — plays  a  prominent  part  in  the  pro- 
cesses of  the  living  body,  and  is  of  importance 
for  distribution  and  action.  I  would  again  in- 
sist upon  the  fact  that  in  lecithid-formation  there 
results,  from  the  reaction  of  two  non-poisonous 
substances  upon  one  another,  a  product  which 


ON  SPECIFIC  THERAPEUTICS.  27 

behaves  absolutely  differently  from  these.  It 
is  not  unnecessary  to  lay  special  stress  upon 
this  point,  for  repeated  attempts  have  been 
made  recently  by  Michaelis  and  Rona  to  draw 
a  parallel  between  the  process  of  lecithid-for- 
mation  and  certain  phenomena  of  colloid- 
absorption  ;  however,  the  tertium  comparationis 
of  such  conclusions  consists  solely  of  analogies 
of  the  most  formal  kind,  and  the  above-sketched 
important  fundamental  fact  is  absolutely  un- 
touched. The  study  of  the  lecithids  from  the 
chemical  point  of  view  has  shown  that  in  them 
we  have  a  field  in  which  the  phenomena  of 
immunity  and  those  of  pure  chemistry  meet, 
and  the  hope  can  therefore  be  cherished  that 
we  may  thus  obtain  a  nearer  insight  into  the 
chemical  peculiarities  of  antigens  and  anti- 
bodies. Already  the  large  mass  of  facts  col- 
lected shows  how  fruitful  the  investigation  into 
chemical  structure,  and  the  questions  which 
arise  therefrom  as  to  distribution,  are  for  the 
analysis  of  immune  substances  and  their  re- 
actions. 

As  to  the  biological  factor  in  the  formation  of 
antibodies,  it  has  been  shown,  by  the  recent 
investigations  of  Pfeiffer  and  Wassermann,  that 
a  part  of  the  process  takes  place  in  the  obscure 


28  EXPERIMENTAL  RESEARCHES 

province  of  the  physiology  of  stimulation. 
Light,  however,  has  been  thrown  on  the  sub- 
ject of  the  specificity  of  reactions  by  the  view  I 
have  expressed  that  the  receptors  of  the  cell- 
protoplasm  are  the  seat  of  the  process,  and  that 
their  regeneration  and  elimination  are  the  con- 
sequences of  this.  Supposing  these  processes 
to  occur  in  the  normal  organism,  and  to  be 
merely  intensified  in  the  case  of  active  immuni- 
sation, it  is  possible  to  understand  that  antibodies 
of  the  most  varied  kinds  may  exist  in  the  serum 
of  the  normal  organism,  and  also  to  comprehend 
the  processes  of  immunity  by  viewing  them  from 
the  standpoint  of  the  physiology  of  nutrition  and 
metabolism.  Thus  I  am  glad  to  be  able,  by  my 
conception  of  the  problem,  to  come  into  entire 
agreement  with  Metchnikoff.  The  immense 
number  of  exceedingly  various  substances  which 
possess  haptine  characters  in  the  blood  serum, 
substances  of  whose  existence  at  one  time  one 
did  not  even  dream,  is  thus  to  be  explained  as 
an  expression  of  a  many  sided  and  differentiated 
action  of  the  most  varied  organs.  One  may 
already  by  simple  means  differentiate  the  mul- 
titude of  serum  substances  into  antitoxins, 
amboceptors,  agglutinins,  precipitins,  opsonins, 
complements,  ferments,  antiferments,  etc.,  but  a 


ON  SPECIFIC  THERAPEUTICS.  29 

deeper  study  of  the  subject  shows  that  each  of 
these  divisions,  in  its  turn,  consists  of  a  multi- 
tude of  functionally  different  components,  and 
thus  a  pluralistic  view  of  the  observed  pheno- 
mena is  the  only  justifiable  one.  Although  in 
some  quarters  the  endeavour  is  still  made  to 
reduce  everything  to  the  most  simple  form,  I 
believe  that  such  a  rudimentary  way  of  looking 
at  things  is  not  justified  by  the  appreciably 
complex  character  of  natural  phenomena  and 
vital  processes ;  for  we  see,  in  the  investigation 
of  immunity,  that  when  earlier  opinions,  based  on 
experiment,  must  be  replaced  by  newer  ones,  the 
process  takes  place  always  by  the  substitution 
of  a  complex  conception  in  place  of  a  simple 
one;  I  would  remind  you  of  Buchner's  idea 
regarding  alexin,  which  had  to  give  way  to  the 
proved  fact  that  all  cytotoxins  have  a  complex 
nature  ;  and  also  I  would  remind  you  of  the 
anti-complements,  which  we  had  supposed  to  be 
simple  bodies,  while  it  is  now  known  that  anti- 
complementary  action  is,  as  a  rule,  the  result  of 
the  concerted  action  of  two  substances.  In  the 
case  of  the  complements,  too,  in  the  light  of 
Ferrata's  researches,  we  must  assume  that  the 
conception  of  these  as  simple  substances  is 
wrong.  The  more  readily,  then,  may  we 


30  EXPERIMENTAL  RESEARCHES 

assume  the  existence  of  a  multitude  of  substances 
as  the  cause  of  the  various  actions  which  are 
exerted  by  one  and  the  same  blood  serum,  a 
multitude  whose  existence  has  in  numerous 
cases  been  proved.  Objections  which  have  been 
raised  by  several  observers,  especially  by  Bordet, 
against  our  method  of  proof,  and  which  consist 
in  stating  that  in  every  experiment  the  substance 
(whose  unity  is  assumed)  has  been  injuriously 
affected,  and  in  attributing  any  difference  to  the 
varying  degree  of  sensitiveness  of  the  various 
test-substances  alone,  cannot  be  justified ;  for, 
if  one  takes  the  trouble  to  work — as  I  have 
always  urged  that  one  should  do  — quantitatively, 
such  sources  of  error  are  immediately  excluded 
from  our  conclusions.  And  even  in  spite  of 
these,  especially  in  the  case  of  the  proof  of  the 
multitude  of  complements,  in  many  cases  one 
has  been  able,  by  employing  means  of  the  most 
varied  kind,  to  obtain  either  the  loss  of  a  certain 
function,  or  an  absolutely  disproportionate 
change  of  degree  in  isolated  functions.  In  the 
plurality  of  haptines  present  in  the  serum  we 
have  a  wide  field  open  for  more  profound 
observation  of  the  mechanism  of  receptor- 
metabolism,  of  the  laws  governing  variations, 
and  the  influences  which  bring  these  about,  a 


ON  SPECIFIC  THERAPEUTICS.  31 

field  from  which  new  light  will  be  shed  on 
human  pathology  and  clinical  medicine.  Suc- 
cessful work  in  this  field  must  proceed  on  a 
broad  basis.  One  would  have  first  to  make 
exact  observations  regarding  a  large  number  of 
functions  of  human  blood  serum,  and  then  one 
would  have  to  investigate  systematically  in 
cases  of  all  sorts  of  diseases,  anomalies  of 
nutrition,  etc.,  the  causes  of  departure  from  the 
normal,  as  to  whether  these  result  from  the 
failure  of  certain  functions,  or  from  the  existence 
of  new  functions  acting  under  pathological  con- 
ditions. Thus,  without  doubt,  would  be  detected 
differences  in  the  sum  of  the  functions  of  the 
cell,  and  this  section  of  the  physiology  and 
pathology  of  the  blood  might  be  named  the 
blood  canon. 

I  firmly  believe  that  by  extensive  research  we 
shall  find  that  there  exist  great  differences,  the 
result  of  biological  laws,  and  these  will  permit 
us  to  come  to  correct  conclusions  as  to  the 
origin  of  certain  substances  in  the  cell,  and  to 
apply  these  conclusions  to  diagnosis  and  thera- 
peutics. Of  course,  the  united  action  of  many 
observers  in  many  institutes,  and  the  closest 
relations  between  clinical  and  laboratory  work, 
are  needful  in  order  that  progress  may  be  made 


32  EXPERIMENTAL  RESEARCHES 

in  the  direction  indicated.  The  recent  work  of 
Wassermann,  who  by  means  of  complement- 
fixation,  was  able  to  prove  the  existence  in 
the  blood  serum  of  anti-bodies  for  certain 
nutritive  substances  (glycogen,  albumoses, 
peptones,  etc.),  and  to  obtain  an  increased  con- 
centration of  these  by  increased  doses  of  the 
nutritive  substances,  appears  to  me  to  be  very 
promising.  In  the  case  of  pathogenetic  or  patho- 
gnomonic  questions  it  does  not  appear  to  be 
of  use  to  seek  for  those  haptines  which  may  be 
present  in  the  blood  as  the  result  of  immunisa- 
tion ;  for  in  their  case  one  would  either  find 
differences  that  are  but  slightly  marked,  or,  if 
one  found  sufficiently-marked  differences,  one 
would  have  to  be  very  careful  in  drawing  con- 
clusions from  them.  It  would  be  better,  there- 
fore, to  avoid  using  as  test  objects  those  sub- 
stances which  are  already  present  in  the  normal 
body,  or  gain  entrance  to  it  by  infection.  In 
order  to  be  able  to  draw  absolutely  correct  con- 
clusions as  to  the  relations  existing  between 
certain  substances  in  the  serum  and  the  normal 
or  pathological  activity  of  organs,  one  ought  to 
choose  cells  or  other  elements,  regarding  which 
one  may  assume  that  they  never  come  into 
relation  with  the  human  body  in  a  natural  way. 


ON  SPECIFIC  THERAPEUTICS.  33 

We  have  a  small  beginning  in  this  direction, 
I  think,  in  the  research  which  I  carried  out 
with  Wechsberg ;  we  compared  the  behaviour 
of  human  blood-serum  towards  the  trypanoso- 
mata  in  the  case  of  healthy  and  diseased  indi- 
viduals, and  we  found  that  in  cases  of  liver 
disease  the  amount  of  trypanosomicidal  sub- 
stances in  the  serum  is  markedly  decreased,  as 
will  be  seen  from  the  subsequent  table. 

After  Laveran  had  by  his  researches  shown 
that  the  serum  of  man  and  of  a  few  species  of 
monkeys  had  a  trypanosomicidal  influence  which 
was  not  possessed  by  the  sera  of  other  animals, 
it  appeared  worth  while  to  pursue  these  re- 
searches further,  and  to  study  this  action  quan- 
titatively, and  when  influenced  by  various 
conditions.  For  this  purpose  we  employed  a 
strain  of  the  trypanosoma  of  mat  de  caderas,  two 
or  three  control  animals  being  also  employed  in 
each  case,  which  succumbed  at  the  latest  on 
the  fifth,  and  generally  on  the  fourth  day.  The 
animals  were  injected  with  equal  quantities  in 
a  similar  manner,  and  as  soon  as  the  parasites 
appeared  in  the  blood  (on  the  second  day)  the 
curative  serum  was  injected.  By  this  means 
we  obtained  a  titration  of  a  number  of  human 
sera,  regarding  which  I  shall  only  give  the 

D 


34  EXPERIMENTAL  RESEARCHES 

following  particulars  as  to  the  results  obtained 
with  small  doses. 

As  Laveran  had  shown,  the  normal  serum 
caused  the  parasites  to  disappear,  but,  after 
a  varying  period,  they  again  made  their  appear- 
ance and  generally  soon  afterwards  caused 
death.  In  cases  in  which  ^  to  T^-  c.c.  of  serum 
was  injected,  the  results  in  the  majority  of  sera 
tested  were  extraordinarily  constant,  in  the 
other  cases  death  occurred  between  the  tenth 
and  fourteenth  day. 

The  cases  were  as  follows : — 

Normal  Serum  I.,  death  on  the  twelfth  day. 

Normal  Serum  II.,  death  on  the  twelfth  day. 

Diabetes  mellitus,  death  on  the  twelfth  day. 

Acromegaly,  presumably  between  the  tenth 
and  eleventh  day  (0*0625  c.c.  caused  death  on 
the  ninth  day). 

Concretio  cordis,  death  on  the  eleventh  day. 

Colica  saturnina,  death  on  the  eleventh  day. 

Polycythasmia  rubra,  death  on  the  twelfth 
day. 

Carcinoma  of  stomach  with  metastases  in  the 
liver,  death  on  the  thirteenth  day. 

Peritoneal  tuberculosis,  death  on  the  thir- 
teenth day. 

Leucaemia  myelogenica,  death  on  the  four- 
teenth day. 


ON  SPECIFIC  THERAPEUTICS.  35 

In  the  cases  of  liver  affections,  on  the  other 
hand,  the  following  results  were  obtained  : — 

(1)  Carcinoma  of  the  bile  ducts  with  complete 
bile  stasis:    0*5 — ro  c.c.  serum,  death   on  the 
fifth  day ;  2*0  c.c.  serum,  death  on  the  eleventh 
day. 

(2)  Carcinoma   of  the   stomach,   with  jaun- 
dice,  0*1 — 0*25  c.c.   serum,   death  on  the   fifth 
day. 

(3)  Alcoholic  cirrhosis  of  the  liver,  0*125  c.c. 
serum,  death  on  the  sixth  day. 

(4)  Biliary  cirrhosis  with  jaundice,  0*125  c.c. 
serum,  death  on  the  seventh  day. 

(5)  Alcoholic  cirrhosis  of  the  liver,  0*125  c.c. 
serum,  death  on  the  eighth  day. 

(6)  Biliary  cirrhosis  with  jaundice,  0*125  c.c. 
serum,  death  on  the  thirteenth  day. 

Thus  there  was  observed  in  every  instance, 
with  the  exception  of  case  6,  a  distinct,  though 
varying,  deficiency  in  the  trypanosomicidal  pro- 
perties of  the  serum,  and  that  this  deficiency 
was  not  merely  an  apparent  one,  produced  by 
the  presence  of  inhibiting  substances,  e.g.,  the 
products  of  bile  stasis,  was  shown  by  experi- 
ments in  which  a  mixture  of  equal  parts  of  the 
serum  from  case  i  and  from  the  acromegaly 
case  were  injected :  0*5  c.c.  of  the  mixture, 

D2 


86          EXPERIMENTAL  RESEARCHES 

death  on  the  sixteenth  day ;  0-25  c.c.  of  the 
mixture,  death  on  the  tenth  day. 

Naturally  one  can  only  expect  to  find  such 
marked  differences  in  the  case  of  those  sub- 
stances which  owe  their  origin  to  a  certain 
organ  or  combination  of  organs.  If  the  place 
of  origin  of  other  haptines  is  widely  diffused 
throughout  the  connective  tissue  of  the  organ- 
ism, one  can  scarcely  hope  in  such  a  case  to 
achieve  much  of  value  for  diagnostic  purposes. 
An  extensive  organisation,  which  does  not  con- 
fine itself  to  investigation  of  a  single  haptine- 
substance,  or  indeed  to  a  few  such,  is  therefore 
necessary,  in  order  that  more  exact  analyses 
may  be  made,  and  results  of  a  practical  value 
be  obtained. 

Looking  back  upon  what  I  have  said,  you  will 
see  that  it  is  the  principle  of  distribution  which 
governs  the  processes  resulting  in  active  im- 
munisation. The  antibodies — the  protective 
substances  in  the  serum — all  possess  the  power 
of  reacting,  with  maximum  chemical  energy, 
with  their  corresponding  antigen,  as,  e.g.,  in  the 
anchoring  of  bacterial  cells.  This  anchoring  is 
a  necessary  preliminary  for  further  reaction, 
which  may  be  of  the  most  varied  kind. 
We  are  acquainted  with  a  number  of  such 


ON  SPECIFIC  THERAPEUTICS.  37 

haptines  or  antibodies,  of  which  the  following 
are  examples : — 

(1)  The  agglutinins,  which  cause  clumping  of 
the  cells. 

(2)  The  amboceptors,  which  play  the  part  of 
carriers  in  the  action  of  the  complement. 

(3)  The  opsonins,  which  render  bacteria  liable 
to  be  seized  by  the  phagocytes  ;  also  those  hap- 
tines which  are  directed  against  the  contents, 
or  metabolic  products,  of  bacteria. 

(4)  The  antitoxins. 

(5)  The  anti-endotoxins,  which  are  directed 
against   the   endotoxins,   to   our   knowledge  of 
which  Macfadyen,  whose  early  death  the  scien- 
tific world  deplores,  has  contributed  so  much. 

(6)  The  precipitins. 

(7)  The   antiferments,    which     are     directed 
against  certain  ferments  of  the  bacterial  cells, 
e.g.,  pyocyanase. 

There  is  no  doubt,  however,  that  many  more 
haptines  exist.  In  order  to  obtain  an  idea  of  the 
extreme  diversity  of  the  phenomena  which 
cause  immunity,  one  must  look  for  other 
substances  whose  functions  are  those  which 
characterise  the  haptines — the  substances,  for 
example,  which  prevent  cell  division,  or  those 
which  combat  the  biological  adaptation  of 


38          EXPERIMENTAL  RESEARCHES 

bacteria.  The  possibilities  which  I  have  here 
indicated  appear  to  be  limitless,  and  the  need 
for  study  in  this  direction  is  evident. 

I  would  here  express  my  dissent  from  a  pre- 
judice which  often  makes  itself  felt,  to  the  effect 
that  in  this  matter  there  exists  a  profound  con- 
tradiction between  humoral  and  cellular  im- 
munity. As  a  matter  of  fact,  to  assume  that 
the  action  of  antibodies  is  merely  a  process 
of  humoral  pathology,  is  to  put  an  artificial 
construction  on  the  facts  observed :  for  the 
side-chain  theory  is  founded  upon  the  view  that 
the  antibodies  are  purely  and  simply  the  pro- 
duct of  cellular  secretion,  and  that  with  their 
appearance  in  the  blood  there  are  associated 
changes  in  the  cells  which  correspond  to  the 
phenomenon  of  serum  immunity.  That  the 
action  of  antibodies  takes  place  in  the  juices  of 
the  organism  is  an  incontestable  fact,  which, 
however,  in  view  of  the  cellular  processes  which 
give  rise  to  it,  cannot  with  justice  be  claimed  to 
be  evidence  in  proof  of  the  correctness  of 
humoral  pathology,  otherwise  we  must  consider 
the  action  of  ferments  to  be  one  of  humoral 
physiology. 

In  the  Protean  forms  of  the  phenomena  of  im- 
munity, of  course,  the  action  of  haptines  by  no 


ON  SPECIFIC  THERAPEUTICS.  39 

means  excludes  phagocytosis ;  destruction  of 
the  bacteria  outside  the  cells  and  their  assimi- 
lation by  the  phagocytes  are  processes  which 
may  take  place  alongside  each  other,  and,  by 
their  simultaneous  action,  increase  the  protec- 
tive power.  A  special  proof  of  the  importance 
of  the  study  of  haptines  appears  to  me  to  be  the 
fact  that — as  the  opsonin  theory,  which  we  owe 
to  Sir  Almroth  Wright,  has  made  more  evident, 
specific  haptine  reactions  form  the  basis  also  of 
phagocytosis,  which  Metchnikoff  has  studied  in 
so  masterly  a  manner.  The  opsonins  and  cyto- 
tropic  substances  render  the  bacteria  liable  to 
attack  by  the  phagocytes,  and  here  we  have  a 
field  in  which  humoral  and  cellular  processes 
meet.  One  cannot,  however,  say  that  the 
possible  causes  of  immunity  are  confined  to 
haptine  action  and  phagocytosis.  Perhaps  the 
atreptic  view,  by  which  differences  of  degree  in 
avidity  on  the  one  side  or  on  the  other  are 
presumed,  is  correct  in  many  cases  in  which 
other  influences  are  at  work.  This  view  of  the 
case  I  shall  treat  more  fully  when  I  come  to 
speak  of  carcinoma. 

The  immunity  of  an  animal  is,  therefore,  ex- 
plained as  being  due  to  the  great  energy  of  the 
cells  of  its  body,  which  are  able  to  appropriate 


40  EXPERIMENTAL  RESEARCHES 

nutritious  substances  for  themselves,  and  in  so 
doing  to  deprive  parasites  of  them.  The  oppo- 
site condition  must  be  due  to  a  certain  dis- 
posing influence,  and  immunity  of  the  parasites 
must  be  a  condition  of  the  cause  of  infectivity. 
The  bacterial  cells  may  in  the  same  way  be 
immune  against  haptine  substances,  and  may 
withstand  the  action  of  the  serum. 

Thus  there  exist  unstable  relations  between 
immunity  and  infection,  and  between  parasite 
and  host,  relations  which  may  depend  on  the 
most  varying  influences,  and  which  lead  up  to 
the  phenomena  of  reversible  action,  which  calls 
for  further  study. 

One  cannot,  therefore,  go  to  work  in  a  one- 
sided way  when  analysing  and  judging  the 
various  forms  of  phenomena,  but  must  carefully 
consider  together  all  the  factors  in  question. 
The  study  of  every  possibility  will  bear  fruit 
and  make  for  an  understanding  of  the  processes 
of  infection  and  immunity.  I  believe,  however, 
that  I  have  shown  the  influence  exerted  by 
the  haptines  upon  the  cause  of  infection  is  of 
great  importance,  not  only  when  these  are 
viewed  as  destroyers  of  the  cause  of  infection 
outside  the  cells,  but  also  when  viewed  in 
connection  with  the  results  of  their  anchoring 


ON  SPECIFIC  THERAPEUTICS.          41 

power,   chief  among  which    at   present   stands 
phagocytosis. 

It  is  our  task  to  advance  by  a  more  accurate 
and  more  extensive  study  of  all  the  haptines 
and  their  actions,  and  in  the  first  place  we  must 
gain  a  knowledge  of  the  influences  exerted  upon 
the  causes  of  infection  by  the  distribution  and 
action  of  dissolved  substances  whose  action  is 
cytotropic,  so  that  we  may  obtain  a  nearer 
insight  into  the  manifold  secondary  phenomena 
which  arise  from  them. 


42          EXPERIMENTAL  RESEARCHES 


LECTURE   II. 

ON  THE  ATREPTIC  FUNCTION. 

IN  my  first  lecture  I  dealt  with  the  anchoring 
phenomena  exhibited  by  the  different  kinds  of 
parasitotropic  substances,  which  thus  aid  the 
body  in  the  process  of  recovery,  and  I  chiefly 
discussed,  in  their  historical  sequence,  the  three 
therapeutically  important  agents,  the  antitoxins, 
the  bacteriolysins  and  the  opsonins  of  Wright. 
I,  however  indicated,  that  with  these  substances 
the  possibilities  were  not  yet  exhausted.  To- 
day I  shall  speak  of  a  different  series  of  processes 
which  may  aid  the  organism  to  fight  its  adver- 
saries, processes  of  a  more  passive  nature,  in 
which  a  secretion  of  active  attacking  substances 
does  not  take  place. 

You  will  remember  that  in  the  early  days 
of  immunity  the  exhaustion  theory  played  an 
important  role.  Pasteur  thought  that  when 
the  body  overcomes  an  infection,  there  are 
removed  from  it  certain  substances  necessary 


ON  SPECIFIC  THERAPEUTICS.  43 

for  the  development  of  that  particular  bacterial 
species ;  should  the  same  kind  of  bacterium  again 
penetrate  into  an  organism  thus  modified,  it 
would  not  find  those  substances  necessary  for 
its  growth,  and  thus  a  new  infection  could 
not  occur.  This  theory  has  of  late  years,  and 
especially  since  the  discovery  of  the  different 
kinds  of  antibodies,  ceased  to  be  of  importance 
in  practical  medicine.  In  point  of  fact,  it  is 
hard  to  imagine  that  in  the  living  body,  as  a 
result  of  some  infective  disease,  which  need 
not  have  produced  any  serious  disturbances, 
there  should  have  occurred  a  complete  and  per- 
manent disappearance  of  certain  chemical  sub- 
stances. That  during  disease  the  internal 
secretions  should  become  disturbed,  and  that 
possibly  at  this  time  certain  cellular  products 
should  be  temporarily  removed  by  excessive 
consumption  and  insufficient  nutrition,  is  pos- 
sible and  even  probable,  but  it  is  quite  unin- 
telligible how,  after  complete  recovery,  such  a 
state  of  things  could  still  persist.  Yet  this  old 
theory  seems  to  me  to  contain  a  nucleus  of  truth, 
as  is  so  often  the  case.  The  chief  point  of 
Pasteur's  theory  is  that  in  the  modified  body 
the  bacteria  should  not  be  able  to  assimilate 
certain  food  substances.  Now,  Pasteur's  idea 


44  EXPERIMENTAL  RESEARCHES 

is  that  this  could  only  take  place  if  the  substances 
in  question  were  absent ;  this  is  obviously  incor- 
rect. But  this  hypothesis  is  not  necessary  in 
order  to  explain  such  insufficient  nutrition  of  the 
bacteria ;  it  suffices  to  assume  that  those  sub- 
stances may  still  be  present,  but  that  the 
parasitic  agents  in  question  are  incapable  of 
absorbing  them ;  in  other  words,  that  the 
substances  have  ceased  to  be  at  the  disposal  of 
the  bacteria. 

This  phenomenon,  at  the  time  of  my  can- 
cer studies,  I  embodied  in  the  definition  of 
"Atrepsy."  I  will  give  you  a  few  examples 
from  my  researches  which  will  make  clear  what 
I  mean  by  this  definition,  and  I  will  begin  with 
a  fairly  simple  case,  viz.,  that  of  the  cobra 
venom. 

This  poison  produces  in  the  body  a  num- 
ber of  very  different  injuries,  e.g.,  it  affects 
the  nervous  centres,  the  subcutaneous  tissue, 
the  red  blood  corpuscles,  the  endothelia,  etc. 
But  whilst  the  manifold  pathological  condi- 
tions produced  in  the  body,  e.g.,  by  corrosive 
sublimate  or  any  other  well-defined  chemi- 
cal substance,  are  in  every  case  the  effect 
of  one  substance  on  different  organs — as,  for 
instance,  nephritis,  inflammation  of  the  salivary 


ON  SPECIFIC  THERAPEUTICS.  45 

glands  and  necrosis  of  the  intestinal  mucosa 
are  the  result  of  the  one  poison,  corrosive 
sublimate, — the  case  is  entirely  different  with 
snake  venom,  for  there  each  separate  and  indi- 
vidual effect  is  the  result  of  a  different  individual 
poison.  Thus,  one  can  prove  with  absolute 
certainty  that  the  effect  on  the  nervous  tissues 
is  produced  by  the  neurotoxin,  that  on  the 
blood  corpuscles  by  a  hsemolysin,  and  the 
inflammatory  changes  by  a  special  endothelio- 
toxin.  It  has  been  shown  that  those  components 
of  snake  venom  which  attack  the  red  blood  cor- 
puscles are  present  in  such  a  form  that  by 
themselves  they  do  not  suffice  to  destroy  them. 

By  following  up  the  researches  of  Flexner 
and  Calmette,  my  former  assistant  and  friend, 
Dr.  Kyes,  has  succeeded  in  throwing  some  light 
on  these  difficult  subjects.  He  proved  that  the 
haemolytic  component  of  the  cobra  venom  is  an 
amboceptor,  which,  however,  differs  from  the 
bacteriolytic  amboceptors  in  not  combining  with 
the  complements  of  the  blood,  but  which  enters 
into  union  with  a  chemically  well-defined  sub- 
stance, lecithin. 

By  shaking  cobra  venom  solutions  with  a 
solution  of  lecithin  in  chloroform,  one  can  show 
that  the  whole  haemolytic  toxin  passes  quanti- 


46          EXPERIMENTAL  RESEARCHES 

tatively  into  the  chloroform,  whilst  the  watery 
portion  has  retained  the  whole  of  the  true 
poisonous  principle,  viz.,  the  neurotoxin.  From 
the  chloroform  solution  one  can  isolate  the 
active  hsemolytic  principle  by  precipitation  with 
ether  ;  it  can  thus  be  obtained  in  the  form  of 
a  white  powder,  which,  on  chemical  analysis, 
gives  figures  which  almost  exactly  fit  the  for- 
mula of  a  mono-stearyl-lecithide.  In  this 
process  there  has,  therefore,  been  split  off  one 
of  the  two  molecules  of  fatty  acid ;  this  can  be 
recovered  quantitatively  from  the  ether. 

The  substance  thus  obtained  is  produced  by 
the  union  of  a  small  quantity  of  the  haemo- 
lytically  active  part  of  cobra  venom  with  a 
relatively  large  number  of  lecithin  molecules. 
It  is  easy  to  prove  that  in  this  we  really  have  to 
do  with  a  chemical  compound,  and  not  the 
result  of  an  absorption  similar  to  that  recently 
described  by  Michaelis  between  rennet  and 
mastix ;  for  it  is  impossible  to  split  up  the 
substance  by  solvents  into  two  components, 
viz.,  mono-stearyl-lecithin  and  the  cobra  venom 
amboceptor,  which  would  be  possible  if  it  were 
only  such  a  mixture.  On  the  other  hand,  in 
conformity  with  its  altered  chemical  character, 
the  substance  has  obtained  new  properties  not 


ON  SPECIFIC  THERAPEUTICS.  47 

found  in  cobra  venom.  For,  in  the  first  place, 
it  is  distinguished  from  the  cobra  amboceptor 
by  having  become  so  completely  thermostable, 
that  solutions  of  this  cobra-lecithide  can  be 
boiled  for  hours  without  losing  a  fraction  of 
their  efficiency,  whilst  under  similar  conditions 
the  original  venom  would  be  rapidly  destroyed.  A 
further  important  property  is  shown  by  the  fact 
that  cobra-lecithide,  even  in  small  quantity,  in- 
stantaneously and  without  any  incubation  period 
dissolves  the  erythrocytes,  whilst  snake  venom, 
even  in  the  presence  of  lecithin,  only  produces 
a  similar  effect  after  several  hours.  The  long 
incubation  period  observed  in  experiments  with 
the  native  poison  is  explained  by  the  fact  that 
the  real  poisonous  body  has  first  to  be  formed 
by  a  synthetic  process,  which,  in  dilute  solutions 
and  at  ordinary  temperatures,  may  naturally 
require  some  time  for  its  completion.  As  you 
see,  I  believe  with  Kyes,  that  the  haemolysis  of 
the  red  blood  corpuscles  is  the  result  of  a  similar 
lecithide  formation. 

It  is  interesting  to  note  the  action  of  cobra 
venom  towards  different  kinds  of  red  blood  cor- 
puscles. It  has  been  found  that  the  corpuscles 
of  the  guinea-pig,  man  and  rabbit,  are  at  once 
dissolved  by  solutions  of  the  poison,  but  that 


48          EXPERIMENTAL  RESEARCHES 

this  is  not  the  case  with  sheep  or  ox  corpuscles. 
These  latter,  however,  are  also  dissolved  if 
a  small  amount  of  lecithin  is  added  to  the 
mixture. 

How  is  one  to  explain  the  fact  that  cobra 
venom  cannot  by  itself  dissolve  certain  kinds  of 
blood  ? 

It  has  been  shown  that  in  all  bloods  lecithin 
is  present  in  fairly  large  quantities.  If  in  spite 
of  that  only  certain  kinds  of  blood  are  affected 
by  cobra  venom,  this  must  be  explained  by  the 
assumption  that  in  every  blood  lecithin  is  not 
present  in  the  free  state,  but  that  it  is  combined 
with  certain  substances  of  the  erythrocyte's 
stroma,  and  that  the  firmness  of  this  union 
differs  considerably  in  the  different  kinds  of 
blood.  That  even  in  the  resistant  erythrocytes 
— e.g.,  those  of  the  sheep — lecithin  is  present  as 
the  activating  substance,  can  easily  be  proved 
by  breaking  down  the  compound  of  proteid  and 
lecithin.  This  can  be  done  by  extracting  with 
alcohol.  The  alcoholic  extract  of  sheep's  blood 
corpuscles  can  be  shown  to  activate  a  mixture 
of  snake  venom  and  sheep's  corpuscles. 

The  results  are  different  if,  instead  of  cobra 
venom,  other  poisons  are  employed.  Thus,  the 
poison  of  Bothrops  lanceolatiis  is  absolutely  unable 


ON  SPECIFIC  THERAPEUTICS.  49 

to  dissolve  any  of  the  above-mentioned  bloods 
without  the  addition  of  lecithin,  whilst  the  poison 
of  Trimesurus  anamalensis  dissolves  only  the  cor- 
puscles of  the  guinea-pig,  that  of  Bungarus 
fasciatus  only  the  corpuscles  of  man  and  guinea- 
pigs,  but  not  others.  From  these  researches 
we  may  deduce  two  facts,  viz.  :  (i)  That  the 
haemolytic  amboceptors  of  snake  poisons  possess 
different  affinities  for  lecithin,  this  affinity  being 
lowest  in  bothrops  venom,  which  dissolves  none 
of  the  before-mentioned  corpuscles,  and  highest 
in  cobra  venom,  which  dissolves  three  of  the 
five  kinds  ;  (2)  that  the  firmness  of  union  of  the 
lecithin  present  in  the  different  blood  species 
varies,  being  highest  in  the  sheep  and  the  ox, 
lower  in  the  rabbit,  still  lower  in  man,  and 
lowest  of  all  in  the  guinea-pig.  You  see  here 
very  clearly  one  of  the  conditions  which  are  of 
importance  for  the  definition  of  atrepsy,  namely, 
that  of  indisposability.  Lecithin  has  an  affinity 
for  certain  constituents  of  the  cell  and  it  also 
has  an  affinity  for  the  constituents  of  the  poison; 
the  difference  between  these  two  affinities 
decides  whether  cobra  lecithide  can  be  formed 
and  haemolysis  can  thus  be  produced.  If  the 
affinity  of  the  constituents  of  the  stromata  is 
higher,  haemolysis  does  not  take  place,  i.e.,  the 

E 


50  EXPERIMENTAL  RESEARCHES 

lecithin  is  not  at  the  disposal  of  the  cobra  ambo- 
ceptor. 

I  will  now  discuss  a  further  similar  case, 
namely,  that  of  certain  phenomena  observed  by 
me  in  the  course  of  my  studies  on  trypanosomes. 
As  some  of  you  may  know,  I  have,  together 
with  my  assistants,  Dr.  Rohl  and  Dr.  Browning, 
proved  that  trypanosomes  can  be  rendered 
resistant  towards  all  those  agents  which  are 
employed  for  curative  purposes.  If,  e.g.,  a 
mouse  infected  with  trypanosomes  is  treated 
with  fuchsin,  the  parasites  disappear,  but 
return  after  a  longer  or  shorter  interval.  If 
the  treatment  is  then  repeated,  a  similar  result 
is  observed.  Thus  this  alternation  of  relapse 
and  treatment  can  be  repeated  several  times, 
though  not  indefinitely,  for  in  course  of  time  the 
effect  of  the  fuchsin  becomes  more  and  more 
unsatisfactory  and  finally  disappears  altogether. 
If  now  the  trypanosomes  are  transferred  from 
such  an  animal  to  normal  mice,  these  parasites 
are  now,  even  in  the  normal  mouse,  found  to  be 
no  longer  capable  of  being  influenced  by  fuchsin. 
There  has  thus  been  formed  a  fuchsin-resistant 
or  "  fuchsin-fast  "  strain.  I  have  chosen  this 
expression  because  I  found  that  such  a  resis- 
tance, once  acquired,  appears  to  remain  un- 


ON  SPECIFIC  THERAPEUTICS.  51 

altered  even  after  as  many  as  a  hundred  succes- 
sive passages.  We  have  up  to  now  produced 
similar  strains  resistant  to  arsenical  preparations, 
to  trypan-red  and  trypan-blue  as  well  as  to 
fuchsin.  In  my  next  lecture  I  shall  enter  more 
fully  into  the  importance  of  these  strains. 

I  will  here  discuss  one  point  only  which  is 
connected  with  to-day's  subject,  viz.,  the 
question  as  to  the  origin  of  the  resistant  strains. 
I  have  made  the  interesting  observation  on  an 
arsenic-fast  strain  which  was  obtained  by  several 
years'  treatment  with  atoxyl,  and  which  was 
then  made  still  more  resistant  by  means  of  a 
very  active  arsenical  preparation  (No.  379), 
which  I  shall  briefly  call  "  Trypocid."  This 
strain  is  distinguished  from  normal  trypanosomes 
in  that  it  is  no  longer  influenced  by  this  highly 
active  arsenical  preparation.  One  would  have 
expected  that  also  in  test-tube  experiments,  it 
would  have  shown  a  high  resistance  towards 
trypocid.  Of  course,  such  an  examination  could 
only  be  carried  out  by  comparing  it  with  other 
strains  of  trypanosomes.  For  obvious  reasons 
I  employed  the  original  strain  from  which  this 
resistant  one  had  been  derived,  and  which  had 
been  cultivated  in  the  laboratory.  I  chose  two 
animals  containing  about  the  same  number  of 

£  2 


52  EXPERIMENTAL  RESEARCHES 

parasites  and  mixed  their  bloods  with  solutions 
of  trypocid  of  different  degrees  of  concentration. 
I  now  observed  the  very  unexpected  phenome- 
non that  in  these  mixtures  the  immune  strain  was 
far  less  resistant  to  higher  doses  of  trypocid  than 
the  normal  one.  Thus  whilst  concentrations  of 
i  in  500  to  i  in  1,000  almost  instantaneously 
killed  the  immune  strain,  the  control  strain 
retained  its  motiiity  unimpaired  in  these  con- 
centrations for  not  less  than  five  minutes. 

We  have  here,  therefore,  one  of  those  striking 
phenomena  which  have  already  been  met  with 
in  the  study  of  immunity  and  which  consist  in 
the  simultaneous  occurrence  of  immunity  and 
hypersensibility  in  one  and  the  same  organism ; 
but  the  case  here  is  somewhat  more  simple, 
since  we  are  working  with  unicellular  organisms, 
and  may  therefore  hope  to  obtain  a  more  accurate 
idea  of  the  case. 

Allow  me  at  this  juncture  to  suggest  to  you  a 
few  fundamental  principles.  In  order  that  a 
given  poison,  e.g.,  the  arsenical  preparation, 
may  act  upon  the  trypanosomes,  it  must  contain 
certain  chemical  groups  which  seize  upon  the 
latter.  These  groups  I  will  distinguish  from 
the  ordinary  receptors,  which  play  an  important 
part  in  the  theory  of  immunity,  by  the  name  of 


ON  SPECIFIC  THERAPEUTICS.  53 

"chemo-receptors."  In  like  manner  the  bodies 
of  the  higher  animals  must  possess  such  chemo- 
receptors  in  certain  organs,  as  they  are  also 
injured  by  the  poison.  If  now  a  mouse  infected 
with  trypanosomes  is  injected  with  the  arsenical 
medicament,  this  substance  will  be  distributed 
between  the  parasites  and  the  organism  of  the 
mouse.  If  the  receptivity  of  the  parasites  is  the 
stronger,  they  will  be  killed  in  the  organism  ;  in 
the  alternative  case,  they  will  not  be  destroyed. 
Consequently  the  curative  result  obtained  when 
experimenting  under  normal  circumstances  re- 
presents also  the  differential  between  two 
avidities ;  i.e.,  if  a  mouse  infected  with  the 
normal  strain  of  trypanosomes  is  injected  with 
the  arsenical  preparation,  the  "  trypanotropic  " 
force  of  the  drug  is  stronger  than  the  "  organo- 
tropic  "  force  ;  we  therefore  obtain  a  curative 
effect  with  doses  which  are  not  injurious  to  the 
organism  of  the  mouse. 

In  the  resistant  strains  this  is  not  the  case, 
since  the  same  doses  show  no  trace  of  action  on 
the  parasites.  One  might  imagine  that  this 
result  was  due  to  the  trypanosomes  having  lost 
their  chemo-receptors  :  but  it  is  not  necessary 
to  make  this  assumption,  and  Nature  has  in  its 
wonderfully  complex  mechanism  found  another 


54  EXPERIMENTAL  RESEARCHES 

and  far  more  economical  expedient  than  the 
loss  of  a  perhaps  necessary  chemical  structure. 
It  is  quite  evident  that  the  same  result  could  be 
obtained  if  the  chemo-receptors  of  the  trypano- 
somes  were  so  far  reduced  in  their  affinity  that 
the  proportion  of  distribution  was  altered  in 
favour  of  the  chemo-receptors  of  the  organism. 
That,  indeed,  is  what  takes  place.  Had  the 
chemo-receptors  quite  disappeared,  the  immune 
strains  would  also  in  the  test-tube  experiment 
be  more  resistant  than  the  normal  ones  ;  as  a 
matter  of  fact,  with  certain  preparations  the 
contrary  occurs.*  The  phenomenon  is  most 
easily  explained  by  the  supposition  that  the 
affinity  of  the  chemo-receptors  has  become 
adjusted  in  such  manner  to  the  counterbalancing 
affinity  of  the  mouse  organism,  that  in  the  mouse 
no  more  arsenic  remains  at  the  disposal  of  the 

*  The  fact  that  these  resistant  strains  are,  in  the  test- 
tube  experiment,  affected  even  more  severely  than  the 
normal  ones,  is  the  result  of  the  co-existence  of  resistance 
and  hyper-sensitivity  in  the  parasite's  protoplasm.  Such 
a  combination  of  immunity  and  hyper-sensitivity  has 
repeatedly  been  observed  in  the  course  of  the  immunisa- 
tion of  higher  animals,  and  this  is  now  assuming  increasing 
importance.  It  is  the  more  interesting  to  note  that  the 
same  phenomenon  occurs  also  in  uni-cellular  organisms. 
The  explanation  of  this  observation  will  be  given  later. 


ON  SPECIFIC  THERAPEUTICS.  55 

trypanosomes.  If,  however,  this  counterbalancing 
effect  of  the  mouse's  organism  is  removed,  the 
poisonous  agent  can  with  full  force  seize  the 
trypanosomes.  I  would  even  go  so  far  as  to  say 
that  we  have  to  do  in  this  case  with  a  biological 
adjustment  of  the  greatest  delicacy,  and  that 
Nature  limits  herself  to  the  most  strictly  neces- 
sary gradations  and  never  allows  a  reduction  of 
the  affinity  to  its  minimum. 

As  a  proof  of  this  I  may  mention  a  similar 
biological  observation.  I  sent  my  resistant 
strain  to  the  Liverpool  School  of  Tropical 
Medicine,  where  it  was  found  that  the  atoxyl- 
resistant  strain  showed  the  resistance  as 
described  by  me  only  in  mice  but  not  in  rats. 
This  result  was,  of  course,  very  surprising,  but 
you  will  easily  understand  it  on  the  basis  of  the 
previous  results,  by  the  supposition  that  the 
avidity  of  the  rat's  organism  for  trypocid  is 
inferior  to  that  of  the  mouse.  In  the  rat, 
therefore,  the  trypanocidal  effect  is  preponderant, 
since  the  trypanosomes  are  still  able  to  seize 
upon  the  poison. 

Let  me  now  pass  on  to  a  very  different  field 
of  research.  I  should  be  guilty  of  carrying 
owls  to  Athens,  if  I  were  here  to  speak  in  detail 
of  the  nature  and  importance  of  Jenner's  great 


56          EXPERIMENTAL  RESEARCHES 

discovery,  which  represents  an  epoch  in  our 
campaign  against  disease  and  the  beginning 
of  the  era  of  immunisation.  I  shall  therefore 
enter  only  into  one  question,  which  throws  a 
little  light  upon  that  modification  of  the  variola 
virus  which  is  produced  by  its  passage  through 
the  cow.  As  you  know,  animals  are  also  affected 
with  small-pox-like  diseases  which  are  closely 
related  to  human  variola.  Such  diseases  are 
the  so-called  "  sheep- pox  "  and  "  bird-pox." 
The  latter  affection  has  recently  been  studied 
at  my  Institute  by  Dr.  Sticker  and  Staff-Surgeon 
Marx.  It  is  easily  transferable  by  cutaneous 
inoculation  to  fowls  and  pigeons,  and  produces 
extensive  small-pox-like  hypertrophy  of  the 
epithelium.  In  the  diseased  epithelial  cells 
highly  staining  spherical  cell-inclusions  are 
found,  which  must  be  identified  with  the  cor- 
puscles of  Guarnieri  that  are  found  in  epithelial 
cells  infected  with  small-pox  or  vaccine.  Ani- 
mals which  have  passed  through  the  disease 
have  thus  acquired  a  complete  immunity  against 
subsequent  infections. 

As  was  shown  by  my  assistants,  the  virus  of 
bird-pox  can  be  filtered  through  filter-candles. 
It  can  be  transferred  to  fowls  and  pigeons.  In 
fowls  the  virus  retains  its  pathogenic  properties 


ON  SPECIFIC  THERAPEUTICS.  57 

unaltered  for  any  number  of  inoculations.  But 
the  results  are  very  different  if  one  tries  to 
inoculate  with  the  diseased  products  occurring 
in  pigeons.  For  although  the  inoculations  can 
also  be  carried  out  in  pigeons  for  any  number  of 
times,  yet  in  such  series  the  virulence  for  fowls 
has  completely  disappeared.  You  see,  there- 
fore, that  we  are  here  dealing  with  a  process 
closely  related  to  the  modifications  which  the 
variola  virus  suffers  in  the  organism  of  the  cow. 
The  only  difference  exists  in  the  fact  that  in  the 
one  case  the  virulence  for  the  original  host  is 
only  reduced,  whilst  in  the  case  of  bird-pox  it  is 
completely  destroyed.  In  my  view  this  can  be 
explained  only  in  one  way,  for  it  is  obviously 
impossible  to  suppose  that  by  one  passage 
through  the  pigeon's  organism  the  parasites  in 
question  should  obtain  a  new  set  of  receptors 
capable  of  seizing  upon  antagonistic  bodies 
present  in  the  normal  fowl's  serum.  It  is  far 
more  natural  to  suppose  that  we  have  to  do 
here  with  a  form  of  atrepsy.  It  is  safe  to 
assume  that  the  chemical  composition  of  fowls' 
ano!  pigeons'  tissues  is  not  identical,  and  that 
therefore  the  parasites,  in  their  passage  through 
the  pigeon,  must  assimilate  substances  different 
to  those  assimilated  in  their  passage  through 


58          EXPERIMENTAL  RESEARCHES 

fowls.  Therefore,  that  part  of  the  receptors 
which  deals  with  the  nutritive  substances  in 
the  fowl's  organism  is  not  in  use  during  the 
passage  through  the  pigeon.  In  view  of  their 
great  instability  it  is  possible  that  this  portion 
of  the  receptors  may  become  atrophied,  whilst 
the  receptors  specific  for  pigeon's  substances 
become  correspondingly  increased.  Thus  the 
micro-organism  would  lose  its  power  of  assimi- 
lating certain  substances  of  the  fowl's  organism. 
If  such  a  parasite  were  transferred  back  to  the 
fowl — supposing  one  of  the  specific  constituents 
of  fowls  to  be  necessary  for  its  proliferation— it 
would  no  more  be  able  to  grow  in  the  fowl. 

This  is,  therefore,  a  case  of  the  loss  of  certain 
receptors  which  are  absolutely  necessary  for 
nutrition.  That  such  a  change,  having  been 
once  acquired,  should  be  permanently  trans- 
mitted from  one  generation  to  another,  is 
hardly  surprising  in  view  of  my  recent  obser- 
vations on  the  modifications  of  arsenic-resistant 
trypanosomata.  Obviously,  the  total  loss  of  the 
chemical  structures  in  question  must  render 
such  modifications  irreparable.  Such  charac- 
teristic instances  as  those  in  which  a  single  pas- 
sage produces  a  permanent  loss  of  virulence  for 
a  certain  animal  species,  are  not  very  frequent. 


ON  SPECIFIC  THERAPEUTICS.  59 

Correspondingly  we  may  presume,  that  the 
variola  virus,  when  passing  through  the  cow, 
permanently  loses  certain  atom-groups  which 
cannot  be  regained  ;  I  believe,  however,  that  in 
cow-pox  this  loss  is  of  a  lesser  degree  than  in 
bird-pox. 

On  the  other  hand,  in  bacteriology  we  fre- 
quently find  that  such  alterations  produced  by 
certain  animal  passages  are  not  of  a  permanent 
nature.  Thus  one  can,  by  successively  passing 
streptococci  through  animals  of  one  species, 
obtain  a  maximum  of  virulence  for  that  species. 
It  is  possible,  therefore,  at  will  to  produce  a 
rabbit-strain,  a  mouse-strain,  etc.  But  one  can, 
by  repeatedly  passing  such  a  strain  through 
animals  of  a  different  species,  transform  it  into  a 
different  strain,  and  thus  in  course  of  time 
obtain  from  a  rabbit-strain  a  mouse-strain. 
This  is  therefore  a  case  of  atrepsy  of  the 
receptoral  apparatus  of  the  bacteria  for  the 
animal  species  in  question,  but  this  atrepsy 
differs  from  that  of  the  variations  of  small-pox 
by  not  possessing  a  permanent  character. 

Probably  the  majority  of  so-called  non-patho- 
genic micro-organisms,  if  introduced  into  an 
animal's  body,  perish  by  this  mechanism.  It  is 
not  neccessary  to  assume  the  presence  of  special 


60  EXPERIMENTAL  RESEARCHES 

poisons  in  the  body,  it  suffices  to  suppose  that 
the  bacteria  in  question  do  not  find  the  needful 
means  of  existence  in  the  body  and  therefore 
cannot  multiply.  This  being  the  case,  they 
cannot  for  any  length  of  time  remain  alive  in 
the  body,  for  then  the  latter's  defensive  forces, 
its  phagocytes,  come  into  action  and  destroy 
the  invaders  in  a  non-specific  manner. 

In  the  case  of  the  pathogenic  micro-organ- 
isms it  will,  however,  as  a  general  rule  be  safer 
not  to  attribute  too  great  an  importance  to 
atrepsy.  But  it  is  evident  that  micro-organ- 
isms can  only  be  pathogenic  for  a  certain 
animal  if  they  find  in  it  possibilities  of  nutri- 
tion. Yet,  to  my  mind,  quite  a  number  of 
infections  are  characterised  by  the  fact  that  the 
micro-organism,  with  the  exception  of  only  a 
few  remnants,  becomes  atreptic.  As  an  exam- 
ple of  such  an  occurrence  I  would  mention  the 
fine  researches  of  my  friend,  A.  Neisser,  who 
found  that  monkeys  injected  subcutaneously  or 
intra-peritoneally  with  great  quantities  of  syphi- 
litic virus  became  neither  infected  nor  im- 
munised. 

It  does  not  appear  possible  to  assume  that  in 
the  serum  of  monkeys,  substances  should  be 
present  which  destroy  the  causative  agents  of 


ON  SPECIFIC  THERAPEUTICS.  61 

syphilis.  It  will  be  more  correct  to  imagine 
that  the  delicate  spirochaetae  have  lost  their 
power  of  infecting  because  they  have  found  no 
suitable  nutritive  bodies  in  the  serum. 

On  the  other  hand  we  know,  from  the  funda- 
mental experiments  of  MetchnikofF  and  Roux, 
that  typical  primary  lesions  can  in  apes  be 
obtained  in  any  part  of  the  skin,  in  the  lower 
monkeys  chiefly  in  the  eyebrows  and  penis. 
Infection  could  also  be  produced  by  rubbing 
diseased  tissue  on  to  the  cut  surface  of  the 
testicle.  On  examining  the  inner  organs  of  the 
monkeys,  Neisser  found  the  virus  to  be  present 
only  in  a  few  organs,  especially  the  haemato- 
poietic organs,  viz.,  the  spleen,  the  bone  mar- 
row and  the  lymphatic  glands,  as  well  as  in  the 
testicles,  whilst  all  the  other  organs  proved 
sterile.  For  this  reason  Neisser  thought  that 
the  primary  processes  in  certain  defined  tissues 
were  of  importance  for  the  occurrence  of  the 
generalised  disease.  If  we  follow  this  view,  it 
will  be  most  easy  to  explain  the  state  of  affairs 
by  the  hypothesis  that  the  serum  of  monkeys 
does  not  contain  properties  sufficient  for  the 
nutrition  of  the  spirochaetae,  whilst  in  certain 
cells  of  these  animals,  viz.,  the  epithelia,  the 
testicular  cells  and  the  leucogenic  cells,  sub- 


62  EXPERIMENTAL  RESEARCHES 

stances  permitting  proliferation  of  the  spiro- 
chaetae  must  be  present.  Probably  there  exists 
only  a  minimum  of  such  substances,  auxiliary, 
but  indispensable  for  their  nutrition. 

I  may  here  remind  you  of  the  fact  that  the 
influenza  bacillus,  as  was  shown  by  R.  Pfeiffer, 
is  not  able  to  proliferate  in  ordinary  culture 
media,  but  that  a  trace  of  haemoglobin  is  neces- 
sary for  its  growth.  In  syphilis  I  imagine  the 
case  to  be  somewhat  similar.  All  the  organs 
which  can  be  primarily  infected  with  syphilitic 
virus  would  thus  be  the  carriers  of  this  specific 
auxiliary  substance. 

The  case  is  more  evident,  macroscopically,  in 
a  great  number  of  very  different  affections,  e.g., 
variola  and  vaccinia,  bird's  and  sheep's  pox, 
foot-  and  mouth-disease,  trachoma,  rabies, 
fowl's  pest  and  scarlatina.  In  all  these  infec- 
tions there  are  found  in  the  epithelial  cells  the 
above-mentioned  peculiar  cell-inclusions,  which 
in  small-pox  are  called  Guarnieri's  corpuscles,  in 
rabies  Negri's  corpuscles.  According  to  recent 
investigations  we  are  justified  in  supposing  that 
these  inclusions  do  not  themselves  represent  the 
parasites,  but  that  they  are  derived  from  the 
cells  and  consist,  according  to  von  Prowazek,  of 
plastin  and  nuclease.  Within  these  masses 


ON  SPECIFIC  THERAPEUTICS.  63 

there  would  lie  enclosed  the  exceedingly  minute 
disease-producing  agents,  these  agents  being  in 
general  so  small  as  hardly  to  be  accurately 
recognisable  by  the  microscope,  with  the  excep- 
tion of  the  inclusions  in  trachoma,  where  the 
parasites  are  clearly  visible  and  bear  the  stamp 
of  something  organised.  We  may  safely  as- 
sume that  in  all  these  cases  the  specific  localisa- 
tion of  the  parasites  in  certain  distinct  kinds  of 
cells,  points  to  the  fact  that  in  these  cells, 
notably  the  epithelium  cells  in  small-pox  and 
trachoma,  and  the  ganglion  cells  in  rabies  and 
fowl  pest,  such  specific  auxiliary  bodies  for  the 
parasites  are  present,  whilst  in  all  the  remaining 
parts  the  micro-organisms  would  encounter  con- 
ditions of  atrepsy. 

The  atreptic  immunity,  which  results  as  I 
stated  from  certain  substances  not  being  at  the 
disposal  of  the  parasites,  seems  to  me  to  play 
an  important  role  in  the  study  of  tumours. 

I  may  even  say,  that  I  first  formed  the  idea 
of  atrepsy  as  the  result  of  numerous  experi- 
mental observations  upon  malignant  mouse 
tumours  which  are  of  cardinal  interest  for 
modern  cancer  research.  I  believe  that  a 
number  of  clinical  and  experimental  facts  in 
this  sphere  of  knowledge  can  only  be  explained 
by  this  hypothesis. 


64  EXPERIMENTAL  RESEARCHES 

As  you  know,  mouse  cancers  are  tumours 
showing  a  far-reaching  analogy  to  human 
cancer,  and  it  would  therefore  appear  most 
justifiable  to  regard  the  experiences  gained  with 
them  as  the  solid  foundation  of  an  experimental 
study  of  tumours.  Besides  several  analogies, 
however,  the  mouse  tumours  show  certain 
special  features,  chief  among  which  is  the  mode 
of  formation  of  metastases.  It  is  most  remark- 
able that  the  highly  virulent  carcinomata  which 
have  been  cultivated  in  numerous  generations, 
very  rarely  show  macroscopically  visible  metas- 
tases, whilst  the  slowly  growing  spontaneous  tu- 
mours relatively  more  often,  though  also  not  very 
commonly,  form  large  secondary  nodules  in  the 
lungs.  Our  interest  in  this  peculiar  behaviour 
must  even  be  increased,  since  Haaland  has 
shown  that  microscopical  metastases  are  by  no 
means  uncommon,  but  that  they  almost  always 
remain  below  the  limit  of  macroscopical  visi- 
bility. I  endeavoured  to  solve  this  problem  by 
making,  so  to  speak,  artificial  metastases,  viz., 
by  studying  in  animals  affected  with  an  inocu- 
lated tumour  the  result  of  a  second  inoculation. 
I  found  the  interesting  fact,  that  the  effect  of 
the  second  inoculation  was  inversely  propor- 
tional to  the  energy  of  growth  of  the  primary 


ON  SPECIFIC  THERAPEUTICS.  65 

tumour.  In  rapidly  growing  sarcomata  and 
carcinomata  the  second  inoculation  almost 
always  had  a  negative  result ;  at  best,  the 
second  tumour  remained  far  inferior  in  size  to 
the  primary  one.  Only  in  the  very  slowly 
growing  chondromata  was  there  no  distinct 
difference  in  their  energy  of  proliferation. 
These  results  agree  with  the  following  obser- 
vation, which  has  been  confirmed  thousands  of 
times.  If,  as  is  regularly  done  in  my  Institute, 
the  inoculation  is  carried  out  by  introducing 
the  capillary  tube  at  the  groin  and  pushing  it 
up  as  far  as  the  axilla,  the  greater  quantity  of 
inoculated  material  will  of  course  be  deposited 
at  the  latter  site,  whilst  only  a  small  portion 
will  remain  at  the  groin.  In  the  case  of  the 
rapidly  growing  carcinomata  and  sarcomata  the 
large  principal  tumours  almost  always  develop 
in  the  axilla,  whilst  a  minute  nodule  is  usually 
found  in  the  groin.  In  the  case  of  the  chon- 
dromata, however,  both  tumours  usually  show  a 
fairly  equal  development.  Thus,  in  the  latter 
case,  the  macroscopical  appearance  somewhat 
resembles  that  of  an  hour-glass,  whilst  in  the 
former  it  is  more  like  a  balloon  with  its  car 
attached. 
To  my  mind,  the  explanation  of  this  pheno- 


66  EXPERIMENTAL  RESEARCHES 

menon  is  as  follows :  every  proliferation  depends 
in  the  first  place  on  the  avidity  of  the  cells  for 
the  nutritive  substances.  Normally,  there  are 
certain  well-defined  laws  of  distribution,  which 
guarantee  the  proper  working  of  the  organic 
functions.  The  avidity  of  the  tumour  cells  is  in- 
creased, as  compared  with  that  of  the  body  cells. 
The  more  energetically  a  tumour  proliferates, 
the  more  powerfully  does  it  attract  the  nutrient 
substances  from  the  blood.  In  the  case  of  a 
rapidly  growing  tumour  it  may  therefore  very 
easily  occur,  that  for  such  cells  which  are  under 
very  unfavourable  conditions  of  nutrition,  e.g., 
cells  inoculated  and  metastatically  carried  away, 
there  is  an  insufficient  supply  of  nutrient  sub- 
stances, and  that  they  therefore  either  perish 
from  atrepsy  or  at  least  are  unfavourably  influ- 
enced in  their  growth.  From  this  point  of 
view  it  is  also  quite  evident  that  slowly  grow- 
ing tumours  can  attain  far  greater  dimensions 
than  rapidly  growing  ones,  since  in  the  former 
the  consumption  of  nutrient  matter,  in  spite 
of  their  size,  is  less  than  in  the  latter,  and 
thus  the  entire  organism  is  injured  to  a  lesser 
extent.0 

*  In  connection  with  this,  attention  may  be  called  to  the 
recent  observations  of  Haaland  (Berl.  Klin.  Wochenschr., 


ON  SPECIFIC  THERAPEUTICS.  67 

I  fail  to  understand  how  von  Dungern  can 
think  himself  justified  in  doubting  the  correctness 
of  this  explanation,  on  the  ground  that  hitherto 
the  experimental  proof  of  a  permanent  increase 
of  cellular  avidity  by  increased  nutrition  has  not 
been  adduced.  I  have  never  asserted  that  we 
can  by  artificial  means  permanently  raise  the 
cellular  avidity.  Such  a  power  would  obviously 
involve  the  possibility  of  artificial  tumour  pro- 
duction. There  is  therefore  no  contradiction, 
as  von  Dungern  imagines,  between  my  views 
and  the  facts  that  by  artificial  hyperaemia  better 
nutrition  is  obtained,  and  that,  after  removal  of 
large  parts  of  the  body,  e.g.,  amputation  at  the 
thigh,  the  hypernutrition  of  the  individual  is 
evidenced,  not  by  the  proliferation  of  func- 
tionating epithelial  cells,  but  by  increase  of 
the  adipose  tissue.  From  the  fact  that  the 
increased  avidity  causes  an  increased  attraction 
of  nutritive  material,  it  does  not  follow  inversely 
that  copious  nutrition  must  increase  the 
avidity.  An  indirectly  injurious  effect  of  more 
highly  avid  cells  on  less  avid  ones  can  there- 
fore only  become  evident,  if  the  body  does  not 

1907,  No.  23,  p.  718),  which  show  that  pregnancy  very 
often  produces  a  retarding  influence  on  the  growth  of  such 
tumours. 

F2 


68  EXPERIMENTAL  RESEARCHES 

possess  sufficient  nutrient  matter  to  saturate 
every  avidity.  The  origin  of  the  higher  avidity 
of  the  tumour  cells  is  quite  unknown  to  us ;  for 
this  question  means  neither  more  nor  less  than 
the  last  problem  of  tumour  aetiology. 

An  entirely  different  significance  must  be 
ascribed  to  the  specific  growth-stimulating 
bodies  or  "  hormones,"  for  the  existence  of 
which  we  have  received  irrefutable  proof  chiefly 
by  the  work  of  Starling.  As  you  may  know,  he 
observed  lactation  in  non-pregnant  females  as 
the  result  of  injecting  emulsions  of  embryos. 
But,  of  course,  I  should  never  think  of  asserting, 
as  one  might  be  led  to  think  by  von  Dungern's 
explanation  of  my  views,  that  as  the  result  of 
over-nutrition  a  typical  lactation  might  be  set 
up  in  a  virgin. 

Such  specific  growth- stimulating  bodies  play 
an  important  role  also  in  other  cases,  and  are 
intimately  connected  with  atreptic  immunity. 
Thus  we  know  that  the  influenza  bacillus  cannot 
do  without  haemoglobin  for  its  growth.  There- 
fore it  is  quite  easy  to  cultivate  the  bacillus 
directly  from  the  sputum,  which  almost  always 
contains  small  quantities  of  haemoglobin.  But 
if  we  do  not  artificially  add  haemoglobin  to  the 
sub-cultures,  the  bacteria  very  soon  die  in  them. 


ON  SPECIFIC  THERAPEUTICS.  69 

Specific  auxiliary  growth- substances  we  must 
also  assume  in  all  those  infective  diseases 
which  are  characterised  by  a  marked  localisa- 
tion of  the  poison,  as  in  bird-pox  and  syphilis. 

The  case  is  quite  similar  in  that  form  of 
atreptic  immunity  which  follows  from  my 
experiments  of  inoculating  rats  with  cells  of 
mouse  tumours.  As  you  know,  hitherto  no  one 
has  ever  succeeded  in  transferring  normal  or 
tumour  tissue  to  animals  of  a  different  species. 
The  limits  of  transplantability  coincide  with 
those  of  bastardisation.  The  question,  how- 
ever, now  arose,  as  to  whether  the  same  barriers 
held  good  also  for  our  highly  virulent  tumour 
material.  To  that  end  I  employed  the  rat  as 
the  animal  phylogenetically  most  nearly  related 
to  the  mouse.  In  fact,  if  a  virulent  mouse 
tumour  is  inoculated  into  a  rat,  the  result  is 
quite  different  from  all  hitherto  known  true 
cases  of  transference  of  tissue  outside  a  species  ; 
for  during  the  first  eight  days  the  cells,  both  of 
carcinomata,  sarcomata  and  chondromata,  pro- 
liferate in  the  rat  just  as  they  do  in  the  mouse. 
During  this  time  tumours  arise  from  the  size 
of  an  almond  to  that  of  a  date,  containing  nume- 
rous mitoses  and  microscopically  differing  in  no 
way  from  the  mouse  tumours.  After  that  time, 


70  EXPERIMENTAL  RESEARCHES 

however,  the  limit  of  their  growth  is  reached 
and  there  now  follows  gradual  resorption,  which 
is  concluded  after  another  week  or  two.  If  the 
tumour  at  its  maximum  development  is  trans- 
ferred to  another  rat,  it  does  not  gain  any 
foothold  there,  whilst  if  it  is  re-inoculated  into 
a  mouse  it  again  proliferates  luxuriantly.  It  is 
possible  to  keep  on  carrying  out  this  zig  zag 
inoculation  from  mouse  to  rat  and  from  rat  to 
mouse,  and  again  from  mouse  to  rat,  etc.,  for 
any  length  of  time  without  the  slightest  check 
to  the  energy  of  proliferation  being  encountered. 
The  question  now  arises,  how  it  is  possible  to 
explain,  on  the  basis  of  these  facts,  the  immunity 
of  the  rat  towards  mouse-tumour  cells. 

We  can  at  once  exclude  the  existence  of  a 
natural  immunity  by  antibodies  in  the  rat,  in 
view  of  the  marked  initial  proliferation  of  the 
tumour.  On  the  other  hand  it  would  be  possible 
to  imagine  that  the  resorption  of  the  tumour 
might  be  the  result  of  an  active  immunisation  of 
the  rat.  That  such  immunisation  ultimately 
occurs  may  be  proved  by  the  fact  that  the  result 
of  re-inoculating  a  rat,  in  which  a  first  tumour 
has  been  absorbed,  with  a  second  tumour,  is 
always  negative. 

I  do  not,  however,  consider  it  permissible  to 


ON  SPECIFIC  THERAPEUTICS.  71 

identify  these  two  manifestations  of  immunity. 
For  in  the  first  place  it  is  highly  improbable 
that,  during  the  period  of  rapid  proliferation  of 
the  tumour  in  the  rat's  organism,  any  consider- 
able absorption  of  tissue  elements  should  occur. 
Further,  previous  to  that  period,  a  production  of 
antibodies  has  not  been  proved.  Lastly,  since 
the  tumour,  when  re-inoculated  into  the  mouse, 
never  shows  ever  so  slight  a  reduction  of  viru- 
lence, one  would  have  to  suppose  with  von 
Dungern  that  the  anti-substance  formed  in  the 
rat's  organism  was  activated  only  by  the  com- 
plements of  rats  but  not  of  mice.  This,  again, 
has  up  to  the  present  not  been  proved. 

A  far  simpler  and  more  natural  explanation 
of  all  these  phenomena  is  afforded  by  my  hypo- 
thesis of  atrepsy.  According  to  this,  the  mouse- 
tumour  cells  require  for  their  growth  not  only 
the  ordinary  nutritive  substances  which  the  rat 
can  also  supply  to  them  in  ample  quantity,  but, 
besides  that,  some  well-defined  substance  which 
is  present  only  in  the  mouse's  organism. 

In  the  rat,  then,  these  cells  would  only  be 
able  to  go  on  growing  so  long  as  there  still 
remained  with  them  some  of  the  specific  growth- 
stimulating  substance  that  was  introduced  with 
them  at  the  time  of  inoculation.  When  it  has 


72  EXPERIMENTAL  RESEARCHES 

all  been  used  up,  growth  can  only  be  further 
stimulated  by  giving  a  fresh  supply  of  this  sub- 
stance, e.g.,  by  re-inoculation  into  the  mouse. 

Just  as  it  is  impossible  to  explain  this  immunity 
of  rats  by  antibodies,  one  cannot  thus  explain 
that  form  of  immunity  in  mice  which  is  evidenced 
in  the  number  of  positive  results  following  inocu- 
lation with  different  tumour  strains.  Generally 
speaking,  the  proportion  of  positive  results  for 
one  strain,  with  the  exception  of  unavoidable 
chances,  varies  only  within  narrow  limits. 
Thus,  the  strain  of  carcinoma  which  we  culti- 
vate in  grey  mice  regularly  grows  in  about  20 
to  25  per  cent. ;  Jensen's  tumour,  according  to 
the  publications,  in  about  40  to  60  per  cent., 
our  other  carcinomata  and  sarcomata  in  90  to 
100  per  cent.,  and  our  chondroma  unexception- 
ally  in  100  per  cent.  The  constancy  of  these 
differences  can  never  be  explained  by  the 
assumption  of  antibodies,  but  only  as  the 
expression  of  a  certain  vitality  of  the  tumour 
cells  which  is  constant  for  each  strain. 

The  atreptic  condition  is  most  clearly  shown 
in  the  cases  repeatedly  mentioned  by  Michaelis, 
Bashford  and  Haaland,  where  the  transference 
to  other  races  of  mice  of  such  virulent  tumours 
was  either  quite  impossible,  or  was  only  successful 


OAT  SPECIFIC  THERAPEUTICS.  73 

in  a  very  low  percentage  of  cases.  In  the  latter 
a  gradual  adaptation  to  the  strange  culture 
medium  could  only  with  great  difficulty  be 
obtained. 

From  my  previous  remarks  it  follows  that  the 
increased  avidity  of  the  cells  for  the  food  sub- 
stances is  the  most  important  characteristic  of 
the  tumour  cells.  But  this  increase  does  not 
suffice  to  explain  all  the  phenomena  observed. 
Albrecht  already  insisted  that  for  malignant 
tumours  one  must  admit  not  only  an  increase 
but  an  alteration  in  the  assimilation,  in  such 
manner  that  the  "  structure  materials "  taken 
up  from  the  surrounding  media  must  in  some 
way  be  bound  or  laid  up  "  until  they  had 
reached  an  amount  sufficient  for  the  division 
of  the  cell."  Besides  this  increased  food- 
absorption,  the  result  of  action  of  the  receptors, 
chemiotactic  remote  efforts  must,  to  my  mind, 
play  an  important  role. 

Such  a  phenomenon  is  very  well  shown  by 
the  chondroma  which  has  been  cultivated  for 
many  years  in  my  Institute.  This  tumour  shows 
a  well-marked  chemiotactic  effect  on  the  blood- 
vessels, in  such  manner  that  even  small  inocu- 
lated tumours,  a  week  or  two  old,  shine  blue 
through  the  skin,  whilst  larger  ones  in  their 


74  EXPERIMENTAL  RESEARCHES 

entirety  present  the  appearance  of  a  haemor- 
rhagic  tumour.  This  angiotactic  attraction  of 
the  blood-vessels  is  an  essential  condition  for 
the  growth  of  the  tumours  ;  for  if,  as  is  the  case 
in  intra-peritoneal  inoculation,  these  angiotactic 
properties  cannot  become  active,  or  if  they  have 
been  lost,  as  is  the  case  in  immunised  animals, 
proliferation  remains  very  limited  both  as 
regards  its  duration  and  its  extent,  and  it 
rapidly  ceases  whilst  the  whole  tissue  becomes 
necrotic. 

As  you  see,  I  have  dealt  with  a  number  of 
apparently  very  different  subjects  of  biology  and 
pathology,  which  are,  however,  united  by  a 
common  bond.  We  have  before  us  the  com- 
petition of  the  different  individualities  for  their 
nutrient  materials.  The  majority  of  such 
chemical  compounds  are  organically  bound 
within  the  cell  to  its  constituents.  This  is,  I 
think,  especially  true  of  the  lipoid  bodies,  like 
fat,  lecithin  and  others.  In  this  respect  I  may, 
perhaps,  remind  you  that  normal  tissue,  e.g., 
the  cortex  of  the  kidney,  contains  fat  in  such  a 
hidden  modification,  since  it  shows  fat  granules 
neither  microscopically  nor  by  the  osmic  acid 
reaction.  If  one  examines  a  similar  organ  in 
the  stage  of  fatty  degeneration,  it  shows  macro- 


ON  SPECIFIC  THERAPEUTICS.  75 

scopically  a  white  colour,  and  by  microscopical 
examination  with  osmic  acid  shows  an  enormous 
number  of  fat  granules.  Yet,  by  extracting  a 
normal  and  such  a  diseased  kidney  with  ether 
and  by  examining  the  ether  residue,  Dunham 
showed  that  the  quantities  of  extract  thus 
obtained,  which  is  but  a  mixture  of  fats  and 
lecithin,  is  exactly  the  same  in  both  cases.  In 
this  case,  therefore,  the  occurrence  of  fatty 
degeneration  consists  only  in  the  fact  that  the 
organic  union  between  the  proteids  and  the 
lipoids  has  ceased,  and  that  the  component 
parts  have  been  liberated,  and  thus  rendered 
easily  recognisable. 

These  facts  are  completely  analogous  to  the 
observations  which  I  have  previously  communi- 
cated when  discussing  Ryes'  researches  on 
snake  venom.  I  even  think  it  probable  that 
the  sugars  may,  in  a  similar  manner,  be  chemi- 
cally firmly  connected  with  the  cells,  and  in 
like  way  the  complex  carbohydrates,  e.g.,  gly- 
cogen,  may  well  be  present  in  the  body  in  a 
hidden  form.  That  is  at  least  made  probable 
by  an  observation  of  mine  on  finding  glycocen 
in  the  polynuclear  cells,  viz.,  that  the  normal 
polynuclear  leucocytes  never  show  the  charac- 
teristic reaction  with  iodine,  whilst  it  is  fre- 


76     EXPERIMENTAL  RESEARCHES 

quently  observed  if  some  injury  has  befallen  the 
body.  Thus,  as  you  are  aware,  in  a  number  of 
intoxications  the  leucocytes  give  a  positive 
glycogen  reaction.  Even  the  slightest  stimuli 
may  cause  the  leucocytes  to  split  off  glycogen  in 
their  protoplasm. 

It  will  be  necessary  to  assume  that  all  these 
compounds  are  joined  to  certain  protoplasmic 
groups,  and  that  the  decomposition  of  these 
compounds  is  the  result  of  a  fermentative 
action,  resembling  the  decomposition  of  amyg- 
dalin,  under  the  influence  of  emulsin,  into 
glucose,  hydrocyanic  acid  and  benzaldehyde. 
Further,  it  is  very  interesting  to  note  that  one 
can  often,  by  simple  extracting  substances  like 
alcohol  or  ether,  remove  from  the  cells  fat  in  the 
form  of  substances  which  still  contain  a  proto- 
plasmic component,  although  chemically  they 
would  appear  at  first  sight  to  be  pure  lipoid 
substances.  Such  extracts  have  been  prepared 
from  red  blood  corpuscles  by  Landsteiner,  Bang 
and  Forssmann,  who  found  that  by  injecting 
such  extracts  into  animals  one  can  obtain 
specific  haemolysins.  This  phenomenon,  which 
they  endeavoured  to  use  as  an  argument  against 
my  side-chain  theory,  is  explained  in  the 
simplest  manner  by  Ryes'  observations  upon 


ON  SPECIFIC  THERAPEUTICS.  77 

the  snake-venom  lecithide.  This  lecithide  would 
appear  to  be  a  pure  fatty  substance,  being 
soluble  in  chloroform  and  even  in  toluol  and 
alcohol,  but  as  a  matter  of  fact  it  contains, 
as  I  was  before  able  to  show  you,  a  very  slight 
quantity  of  the  poison  in  chemical  combination. 
And  it  is  this  portion  which  induces  the  bio- 
logical reaction.  The  fact  that  in  spite  of  this 
component  being  of  a  non-fatty  nature,  the  com- 
pound apparently  behaves  like  an  ordinary  fat, 
is  due  to  the  presence  in  it  of  a  great  number  of 
fatty  molecules  which  have  given  to  the  whole 
substance  their  specific  characters. 

I  have  frequently  laid  stress  upon  the  fact 
that  many  nutrient  substances  are  not  present 
in  the  cells  in  a  free  state,  and  that,  therefore, 
they  are  not  at  the  disposal  of  any  invader,  but 
that  a  struggle  is  always  necessary  before  they 
can  be  rendered  accessible.  In  the  case  of 
snake  venom  I  have  shown  that  we  are  dealing 
with  a  simple  difference  between  two  chemical 
avidities.  In  the  case  of  bacteria  the  affair  may 
be  rather  more  complicated,  according  to  the 
occurrence  of  either  of  two  possibilities,  viz. : 
(i)  A  direct  assimilation  in  consequence  of  a 
higher  degree  of  affinity,  or  (2)  an  indirect 
action  by  injury  to  the  cell.  Supposing,  for 


78  EXPERIMENTAL  RESEARCHES 

example,  that  a  microbe  had  penetrated  into  a 
cell,  but  had  not  the  power  of  directly  splitting 
off  the  fatty  bodies ;  then  these  substances 
would  not  be  immediately  assimilable  by  it. 
Yet  the  microbe  might  obtain  possession  of 
them  if  it  secreted  a  poison  injurious  to  the  cell, 
which  would  decompose  the  protoplasm.  In 
such  a  case  the  fat  would  be  liberated,  and 
could  be  assimilated  by  the  micro-organism, 
even  though  the  immediate  affinity  between 
the  two  were  very  low.  At  any  rate,  these 
considerations  may  so  far  be  of  interest  as 
they  touch  upon  an  issue  of  biology  and  patho- 
logy, which  has,  on  the  whole,  been  somewhat 
pushed  into  the  background  of  late  years,  since 
one  has  accustomed  oneself  in  every  infective 
process  to  think  in  the  first  place  of  a  specific 
bactericidal  action  through  the  direct  toxic 
substances  of  the  body,  its  haptines,  etc.  This 
has  led  to  our  neglecting  somewhat  the  simple 
possibility  that  certain  micro-organisms  may 
only  be  able  to  grow  if  certain  conditions  are 
given  for  their  development,  and  that  they  must 
perish  if  these  conditions  are  withheld.  To 
my  mind  this  possibility  is  of  importance  in 
many  respects,  and  is  especially  significant  for 
our  views  on  cancer  immunity.  At  any  rate, 


ON  SPECIFIC  THERAPEUTICS.  79 

we  are  dealing  in  these  questions  with  a  highly 
complex  field  of  research,  in  which  many  possi- 
bilities are  present,  the  most  important  being 
this  difference  of  avidities. 

We  have  previously  seen  that  the  trypano- 
somes  may  alter  their  avidity  for  arsenic,  and  thus 
acquire  an  apparent  immunity.  The  contrary 
may  occur  in  the  case  where  the  substance  in 
question  is  not  a  poison,  but  a  nutritive  body. 
Here  we  should  be  perfectly  justified  in  sup- 
posing the  avidity  of  the  receptor  to  have 
become  increased.  The  same  thing  may  take 
place  with  such  micro-organisms  which  can 
physiologically  diminish  or  increase  their  avidi- 
ties. Thus  in  all  these  cases  the  struggle  lies 
between  the  adaptability  of  the  parasite  and 
that  of  the  host.  The  one  whose  adaptability  is 
the  highest  will  remain  the  victor. 

Of  course  this  struggle  is  to  a  great  extent 
influenced  by  indirect  actions,  consisting  in  the 
secretion  by  each  antagonist  of  dissolved  sub- 
stances hostile  to  the  vitality  and  receptivity  of 
the  other  organism.  On  the  part  of  the  bac- 
teria, these  substances  are  the  toxins  and  the 
dissolved  intracellular  substances  ;  on  the  part 
of  the  body,  the  anti-substances. 

A  further  vole  is  played  by  actions  of  a  pro- 


80          EXPERIMENTAL  RESEARCHES 

tective  and  defensive  nature.  Thus  we  have 
shown  that  bacteria  congregate  in  those  parts 
where  they  find  the  most  favourable  conditions 
of  nutrition,  whilst  the  organism,  both  by  its 
phagocytes  and  by  means  of  encystment,  endea- 
vours to  render  the  pathogenic  germs  harmless 
and  to  eliminate  them.  You  see,  therefore,  that 
this  is  a  war  waged  in  different  fields,  but  in 
which  to  every  action  there  corresponds  a 
reaction.  The  war  is  waged  in  a  three- fold 
manner — by  variations  of  affinity,  by  variations 
in  the  poison,  and  by  localisation. 


ON  SPECIFIC  THERAPEUTICS.  81 


LECTURE   III. 

CHEMO-THERAPEUTIC  STUDIES  ON  TRYPANOSOMES. 

THE  studies  on  trypanosomes,  which  have  of 
late  been  carried  out  with  the  greatest  energy, 
especially  in  the  Institut  Pasteur  in  Paris,  the 
School  of  Tropical  Medicine  in  Liverpool,  and 
the  Speyerhaus  in  Frankfort-on-the-Main,  are 
of  the  greatest  theoretical  and  practical  im- 
portance ;  for  in  this  field  of  study  the  patient 
research  work  of  Experimental  Therapeutics 
has  first  come  into  full  activity,  and  at  the  same 
time  a  basis  has  been  gained  on  which  we  may 
hope  successfully  to  undertake  the  practical 
attempt  of  suppressing  sleeping-sickness.  The 
exceedingly  great  difficulty  of  these  studies  is 
evidenced  by  the  fact  that  hundreds  and  thou- 
sands of  substances  have  to  be  examined  by 
animal  experiments,  before  a  few  producing  a 
therapeutic  effect  can  be  found.  I  myself  have 
in  course  of  time  examined  more  than  600  such 
substances.  From  their  effect  on  animals,  hints 

G 


82  EXPERIMENTAL  RESEARCHES 

may  be  obtained  as  to  what  to  avoid,  and  in 
what  direction  therapeutics  should  advance.  I 
will  not  enter  here  into  the  details  of  my  work, 
but  will  only  give  you  a  general  resume  of  the 
chief  results. 

The  substances  which  have  hitherto  proved 
efficient  in  combating  trypanosome  infections 
can  be  divided  into  three  groups,  viz.  :  —  (i)  The 
group  of  the  basic  triphenyl-methane  dyes ;  (2) 
The  group  of  the  benzidine  dyes ;  (3)  The 
group  of  the  arsenicals. 

The  salts  of  mercury  may  be  used  as  adju- 
vants to  each  of  the  foregoing. 

Among  the  triphenyl-methane  stains,  which 
were  first  employed  by  Wendelstadt,  para- 
fuchsin  is  by  far  the  most  satisfactory.  It  is 
possible,  by  prophylactic  feeding  with  this  drug, 
to  render  mice  resistant  to  trypanosome  infec- 
tions for  a  long  time,  and  I  believe  that  this 
innocent  substance  might  well  be  employed  in 
the  Tropics  for  the  prophylaxis  of  human 
sleeping-sickness. 

As  regards  the  second  type  of  substances, 
belonging  to  the  benzidine  group,  trypan-red 
is  a  cotton  dye  which  shows  the  remarkable 
property  of  staining  mice  an  intense  red,  which 
remains  fast  for  months.  I  have  also  prepared 


ON  SPECIFIC  THERAPEUTICS,  83 

a  number  of  similar  dyes  belonging  to  the  ben- 
zidine  series,  some  of  which  possess  an  even 
more  powerful  action  than  trypan-red.  In 
several  cases  a  blue  dye  belonging  to  the  same 
group,  which  was  prepared  by  Nicolle  and 
Mesnil,  has  proved  still  more  efficient. 

The  value  of  arsenic  acid  which  has  for  a 
long  time  been  employed  in  the  treatment  of 
trypanosome  diseases  was  first  recognised  by 
Laveran.  Later  on  it  was  discovered,  at  the 
Liverpool  School  of  Tropical  Medicine,  that 
atoxyl  was  a  far  more  powerful  substance.  It 
is  prepared  by  treating  aniline  with  arsenic 
acid.  The  makers  believed  it  to  be  an  anilide  of 
arsenic  acid,  i.e.9  a  compound  in  which  the 
arsenic  acid  radical  is  supposed  to  be  attached 
to  the  amido  group  in  a  similar  manner  as  the 
acetic  acid  is  present  in  acetanilide.  Now,  as 
you  all  know,  the  ammonia  radical,  which  in 
aniline  is  very  ready  to  react,  has  completely 
lost  this  property  in  acetanilide.  This  latter 
body  is  in  fact  almost  an  indifferent  compound. 
Similarly,  by  the  view  that  atoxyl  was  the 
anilide  of  arsenic  acid,  any  further  development 
of  this  compound  was  rendered  impossible.  I 
was,  however,  able  to  prove,  together  with 
Dr.  Bertheim,  that  this  compound  is  to  be 

G2 


84  EXPERIMENTAL  RESEARCHES 

regarded  as  something  entirely  different,  namely, 
that  the  amido  group  is  quite  free  and  that  the 
arsenic  acid  radical  is  attached  to  the  benzol 
ring  in  the  para  position.  Atoxyl  must,  there- 
fore, be  regarded  as  the  sodium  salt  of  paramido- 
phenyl-arsinic  acid. 

We  have  obtained  a  great  number  of  sub- 
stances derived  from  it,  and  have  tested  them 
therapeutically.  Thus  we  found  that,  e.g.,  by 
the  introduction  of  the  acetyi  radical  into  the 
amido  group  the  acetyl-amido-phenyl-arsinic 
acid  is  produced,  which  is  far  less  toxic  for  mice 
than  atoxyl.  By  means  of  this  substance  it  is 
even  possible  to  solve  one  of  the  most  difficult 
therapeutic  problems  imaginable.  For  mice 
that  have  been  infected  with  our  most  virulent 
strains,  and  which,  without  treatment,  would 
die  within  three  days,  can  in  two-thirds  of  the 
cases  be  saved  by  this  substance  if  it  is  given 
twelve  to  fourteen  hours  before  death.  Such 
curative  results  have  never  yet  been  published  ; 
for  in  previous  communications  there  were  men- 
tioned almost  exclusively  experiments  carried 
out  at  earlier  periods  of  infection.  In  our  cases 
acetyl-atoxyl  cures  mice  in  nearly  100  per 
cent.  Unfortunately,  acetyl-atoxyl  is  decom- 
posed in  other  animals,  especially  in  the  horse. 


ON  SPECIFIC  THERAPEUTICS.  85 

into  acetic  acid  and  aniline,  and  it  cannot, 
therefore,  be  nearly  as  effective  as  it  is  in  the 
mouse.  Nevertheless,  the  results  obtained  in 
the  mouse  are  so  excellent  that  they  must 
encourage  us  to  energetically  pursue  the  path 
of  these  discoveries. 

I  mentioned  in  my  last  lecture  that  it  is  pos- 
sible to  obtain  strains  of  trypanosomes  which 
are  resistant  to  these  active  substances.  Studies, 
which  I  have  carried  out  with  Dr.  Rohl  and 
Dr.  Browning,  have  shown  this  resistance  to  be 
of  a  very  high  degree.  Thus,  atoxyl-fast  strains 
show  no  sign  of  being  influenced  by  the  highest 
doses  of  atoxyl  which  are  applicable  to  mice. 
I  gave  you  the  explanation  for  this  resistance, 
viz.,  that  it  is  the  result  of  a  decrease  in  the 
avidity  of  the  trypanosomes  for  these  trypano- 
cidal  substances.  Further,  I  pointed  out  that, 
apart  from  this  resistance,  the  parasites'  pro- 
toplasm, although  not  their  nuclei,  had  become 
hyper-sensitive  towards  the  arsenical  prepara- 
tion. Thus  we  meet  with  an  important  instance 
of  association,  in  one  and  the  same  cell,  of 
resistance  and  hyper-sensitivity.  This  associa- 
tion, which  is  of  late  years  proving  to  be  of 
increasing  importance  in  the  question  of 
mammalian  immunity,  is  therefore  present 


86          EXPERIMENT  A  L  RE  SEA  RCHES 

even  in  so  simple  an  organism  as  this  proto- 
zoon. 

Although  in  the  mouse  atoxyl-resistance  usu- 
ally develops  only  after  a  fairly  long  period,  I 
have  occasionally  seen  it  after  a  fortnight.  This 
observation  is  very  important,  because  it  makes 
it  possible  that  the  negative  results  observed 
by  Ayres  Kopke,  Broden,  Rodhain,  Todd  and 
van  Campenhout,  in  cases  of  sleeping-sickness 
which  had  received  a  long-continued  treatment, 
may  also  be  due  to  such  a  resistance. 

In  the  same  way  as  against  atoxyl,  trypano- 
somes  can  also  be  rendered  resistant  to  para- 
fuchsin,  trypan-red  and  trypan-blue,  and  further, 
it  was  shown  in  my  Institute  by  Franke  in  his 
work  with  apes,  that  it  is  even  possible  for  try- 
panosomes  to  become  resistant  to  those  pro- 
tective substances  which  are  formed  in  the  ani- 
mal after  its  recovery  from  a  trypanosome  infec- 
tion. A  similar  discovery  has  recently  been 
made  by  Levaditi  for  the  spirochaetes  of  relaps- 
ing fever.  This  is  therefore  a  general  law,  and 
it  is  especially  important,  because  this  change 
in  the  trypanosomes,  having  once  become  ac- 
quired, remains  an  hereditary  property.  Thus  I 
have  cultivated  for  125  generations  my  atoxyl- 
fast  strain,  without  finding  any  decrease  in  its 


ON  SPECIFIC  THERA PE  UTICS.          87 

power  of  resistance.  We  must  further  note 
that  every  such  resistance  is  specific.  Thus 
the  fuchsin-fast  strains  are  resistant  only  to  this 
substance,  but  not  to  atoxyl  and  trypan-red,  and 
vice  versa.  This  resistance  extends,  however,  to 
chemically  different  substances  of  the  same 
group,  so  that  we  can  in  any  individual  case 
decide  to  which  group  a  given  new  trypano- 
cidal  agent  belongs.  Thus,  e.g.,  the  atoxyl-fast 
strain  is  resistant  also  to  a  number  of  related 
substances.  Among  hundreds  of  trypanocidal 
bodies,  it  is  thus  possible  to  single  out  those 
substances  which  contain  arsenic. 

It  has  further  been  shown  that  the  resistance 
to  trypan-red  and  trypan-blue  is  a  mutual  one, 
in  spite  of  considerable  chemical  differences 
between  these  two  substances,  which  in  fact 
have  nothing  in  common  with  one  another 
except  that  they  contain  naphthalin  rings,  which 
are  substituted  in  a  certain  position  (3,  6)  by 
sulphuric  acid  radicals. 

Thus  we  possess  in  this  specific  resistance,  so 
to  speak,  a  therapeutic  sieve,  a  cribrum  thempeu- 
ticum,  with  which  we  can  undertake  the  classifi- 
cation of  any  new  chemo-therapeutic  substance. 
If  such  a  substance  is  found  to  have  a  destruc- 
tive effect  on  our  three  different  resistant  strains, 


88          EXPERIMENTAL  RESEARCHES 

it  necessarily  belongs  to  a  fourth  chemical 
group.  One  can,  of  course,  materially  simplify 
this  examination  by  employing  strains  that 
have  been  rendered  resistant  to  all  the  groups 
hitherto  known.  Thus  I  have,  together  with 
Dr.  Browning,  obtained  a  strain  which  is  resis- 
tant to  atoxyl,  trypan-red  and  fuchsin.  By 
using  such  a  strain,  a  single  animal  experiment 
suffices  for  the  purpose  of  establishing  any  new 
group  of  such  chemo-therapeutic  agents.  For, 
if  one  injects  the  substance  in  question  to  such  a 
trebly  resistant  mouse,  the  trypanosomes  will 
either  go  on  proliferating — then  the  substance 
must  belong  to  one  of  the  three  known  groups 
— or  the  trypanosomes  are  injured  ;  in  that  case 
we  have  before  us  a  new  type.  As  you  see,  we 
are  therefore  enabled  by  means  of  these  resis- 
tant strains  to  separate  substances  of  different 
modes  of  action  from  one  another,  and  thus  to 
solve  a  problem  which  hitherto  could  not  even 
be  suggested.  A  way  is  thus  shown  us  by 
which  we  may  enter  upon  the  consideration  of 
the  most  intricate  problems  of  pharmacodyna- 
mics  and,  if  I  may  say  so,  obtain  a  fuller  know- 
ledge "  de  sedibus  et  causis  phannaconwn" 

I  also  wish  to   lay  especial   stress   upon   my 
view  that  the  drugs,  also,  are  attracted  by  and 


ON  SPECIFIC  THERAPEUTICS.  89 

bound  to  the  protoplasm  molecule  by  certain 
atom  groupings.  I  am  inclined  to  look  upon 
this  as  somewhat  analogous  to  the  binding  of 
the  toxins  and  of  similar  proteid  bodies.  Yet 
on  the  other  hand,  there  are  fundamental  differ- 
ences between  the  two.  For,  as  I  have  always 
insisted,  the  mode  of  binding  the  toxins  is 
peculiar  in  so  far  as  it  is  the  result  of  a  certain 
kind  of  assimilation  which  obviously  consists  in 
processes  of  a  more  or  less  synthetic  nature. 
These  toxin-receptors  which  produce  immunity 
are  bodies  of  a  more  independent  character, 
and  appear  to  be  especially  destined  for  pur- 
poses of  assimilation.  This  high  degree  of 
independence  is  evidenced  by  the  fact  that,  in 
conformity  with  my  side-chain  theory,  these 
receptors  are  very  easily  reproduced  by  the  cell 
in  excessive  numbers,  and  after  being  separated 
from  the  cell,  find  their  way  into  the  blood. 

I  have  now  formed  the  opinion  that  in  like 
manner  a  part  of  the  chemically  defined  sub- 
stances is  attached  to  the  cell  by  groups 
corresponding  to  these  receptors  ;  these  atom 
groupings  I  will  distinguish  from  the  toxin- 
receptors  by  the  name  of  "  chemo-receptors." 
This  view  is  more  particularly  supported  by 
the  fact  before  mentioned,  that  the  atoxyl-fast 


90          EXPERIMENTAL  RESEARCHES 

strain  is  also  resistant  to  a  number  of  sub- 
stances related  to  atoxyl,  but  otherwise  showing 
widely  different  chemical  characteristics.  Evi- 
dently, therefore,  the  arsenic  acid  radical  here 
represents  the  point  of  attack  which  is  common 
to  this  series  of  substances.  It  is  the  arsenical 
radical  as  such,  which  is  bound  by  the  chemo- 
receptors.  These  chemo-receptors,  must,  how- 
ever, be  regarded  as  of  a  simpler  structure  than 
the  toxin-receptors.  They  do  not  show  a  similar 
degree  of  independence ;  they  cannot  therefore 
become  increased  in  chronic  intoxications,  and 
since  they  are  sessile,  they  cannot  be  thrown  off 
into  the  blood.  The  number  of  such  chemo- 
receptors  for  poisons  which  a  trypanosome  cell 
possesses,  represents  the  number  of  points  of 
attack.  By  means  of  the  resistant  strains  we 
can  count  off  one  by  one  these  groups  that  are 
open  to  attack. 

The  discovery  of  any  trypanocidal  substance 
will  always  be  the  result  of  chance  and  experi- 
ment. Every  point  of  attack  may,  of  course,  be 
liable  to  be  attacked  by  a  host  of  different  bodies, 
all  of  which  have  one  specific  group  in  common. 
It  must  be  the  goal  of  our  experiments  to 
search,  by  systematic  chemical  researches,  for 
the  most  suitable  substances,  and  thus  to  dis- 


ON  SPECIFIC  THERAPEUTICS.  91 

cover  the  "optimum  centres."  This  problem  is 
by  no  means  an  easy  one,  since  according  to 
my  experience  of  many  years,  which  agrees 
entirely  with  that  of  Mesnil,  different  animal 
species  have  different  optima,  and  therefore  the 
work  must  be  specially  done  for  each  species  of 
animals  and  each  kind  of  trypanosomes.  Thus, 
e.g.,  in  the  mouse,  Trypanosoma  gambiense  is  far 
more  easily  attacked  by  arsenical  preparations 
than  the  other  strains  of  animal-pathogenic 
trypanosomes,  whilst  fuchsin  and  its  relatives 
show  an  exactly  opposite  behaviour.  Still,  in 
spite  of  all  these  difficulties,  the  problem  is  not 
insoluble,  since  there  are  only  a  limited  num- 
ber of  animal  species  and  of  trypanosomes  ;  we 
may,  therefore,  confidently  cherish  the  hope 
that  the  united  forces  of  the  observers  who  are 
at  work  on  this  subject  in  various  laboratories 
will  ultimately  succeed  in  attaining  the  victory 
over  sleeping-sickness,  which  is  practically  the 
most  important. 

Especially  with  a  view  to  practical  thera- 
peutics the  knowledge  of  the  different  points 
of  attack  is  necessary,  since  it  furnishes  us 
with  the  possibility  of  fighting  the  disease  by 
the  combination  of  several  chemo-therapeutic 
agents. 


92     EXPERIMENTAL  RESEARCHES 

The  principle  of  this  combinatory  method  of 
therapeutics  is,  to  attack  the  enemy  simul- 
taneously from  two  or  three  sides,  and  thus  to 
produce  a  completely  successful  result  by  the 
combination  of  several  different  substances, 
each  of  which  alone  does  not  show  a  sufficient 
effect.  Thus  it  has  been  found  by  Laveran 
and  by  Franke  that  certain  infections  which  are 
influenced  neither  by  trypan-red  nor  by  atoxyl 
alone,  can  be  cured  if  these  two  substances  are 
used  in  conjunction.  I,  too,  have  in  course  of 
time  repeatedly  met  with  similar  cases,  and  am 
convinced  that  substances  which  by  themselves 
are  not  very  efficient,  may  yet  produce  good  re- 
sults if  they  are  used  as  adjuncts  to  those  more 
powerful,  though  not  completely  curative,  sub- 
stances. Supposing,  e.g.,  a  highly  trypanocidal 
remedy  to  kill  ninety-eight  among  one  hundred 
parasites,  its  administration  would  be  followed 
by  an  instantaneous  improvement,  but  not  a 
definite  cure,  since  the  two  surviving  trypano- 
somes  must  in  course  of  time  produce  a  relapse. 
But  if  one  combined  this  powerful  remedy  with 
another  which,  even  though  much  weaker,  yet 
sufficed  to  kill  just  those  two  surviving  but 
attenuated  parasites,  then  such  a  combination 
would  serve  to  bring  about  the  otherwise  un- 


ON  SPECIFIC  THERAPEUTICS.  93 

attainable  cure.  In  this  respect  a  publication 
from  the  Liverpool  School  of  Tropical  Medicine 
is  most  interesting,  as  it  demonstrates  the 
successful  result  of  the  employment  of  supple- 
mentary doses  of  perchloride  of  mercury  in 
the  atoxyl  treatment  of  animals  infected  with 
sleeping-sickness.* 

For  man  the  combinatory  treatment  is  of  the 
greatest  importance  for  a  further  reason.  The 
complete  sterilisation  of  the  body,  i.e.,  the  total 
destruction  of  every  parasite,  is  often  only  to  be 
accomplished  by  the  administration  of  doses 
which  come  very  close  to  the  lethal  dose.  Such 
a  procedure  directly  endangering  life  may  be 
permissible  in  the  animal  experiment,  but  never 
in  man.  One  is,  however,  justified  in  hoping 
that  it  might  be  possible  to  cure  the  disease 
without  endangering  life  by  the  simultaneous 
administration  of  three,  four  or  five  substances, 
chosen  in  such  a  manner  that  their  actions  are 
concentrated  on  the  parasites,  whilst  in  the 
organism  of  the  vertebrate  host  they  are  dis- 
tributed over  several  different  organs. 

It  is  only  natural  that  modern  therapy  which 

*  The  perchloride  in  these  cases  has  only  the  effect  of 
an  adjuvant,  since  it  has  been  shown  that  its  action  on  the 
trypanosomes,  if  administered  alone,  is  quite  inadequate, 


94          EXPERIMENTAL  RESEARCHES 

is,  as  a  rule,  brought  to  bear  upon  man  under 
circumstances  making  it  very  difficult  to  judge 
correctly  of  the  processes  occurring  during  treat- 
ment, has  in  the  last  decades  worked  chiefly 
with  simple  bodies.  On  the  other  hand,  I 
would  remind  you  that  in  the  prescriptions  of 
the  physicians  of  the  middle  of  last  century,  a 
predilection  for  long  and  complex  prescriptions 
was  evident ;  and  although  nowadays  this  predi- 
lection may  appear  to  us  obsolete,  yet  it  must 
surely  have  sprung  from  a  good  power  of  obser- 
vation, enhanced  by  rich  personal  experience. 
Although  this  former  practice  of  therapeutic 
procedure  may  have  overshot  the  mark,  it  would 
yet  appear  to  contain  a  nucleus  of  truth,  and 
it  has  certainly  received  the  approval  of  science 
through  these  recent  discoveries. 

The  importance  of  combined  treatment  is 
shown,  lastly,  in  the  phenomena  of  resistance 
already  discussed.  The  fact  that  by  frequently 
repeated  administration  of  not  completely 
sterilising  doses,  there  is  gradually  acquired  a 
resistance  to  the  substance  in  question,  makes  it 
especially  desirable  that  the  first  attack  should 
be  as  complete  as  possible.  This  object,  from 
what  I  have  previously  said,  may  probably  best 
be  carried  out  by  a  suitable  combination  of 


ON  SPECIFIC  THERAPEUTICS.  95 

substances.  I  would  like  here  to  call  your 
attention  to  the  fact  that  two  decades  ago  I 
discovered  a  considerable  efficacy  of  methylene 
blue  against  certain  forms  of  malaria.  This 
dye  has  not,  however,  obtained  any  extensive 
employment,  since  its  effect  is  inferior  to  that  of 
quinine.  On  the  ground  of  our  recent  experi- 
ence one  would,  I  think,  be  perfectly  justified 
in  attempting  to  re-inforce  the  attack  on  the 
malaria  parasites  by  employing  combined  doses 
of  quinine  and  methylene  blue. 

Having  now  reached  the  end  of  my  lecture, 
will  you  allow  me  once  more  to  call  your 
attention  to  the  fact  that  the  importance  of 
these  trypanosome  studies  is  a  twofold  one ; 
first,  for  theoretical  reasons,  because  they  afford 
us  a  deep  insight  into  the  finest  mechanism  of 
the  action  of  the  drugs ;  and  second,  for  prac- 
tical reasons,  since  by  the  methods  of  research 
employed  and  especially  by  the  development  of 
the  combined  treatment,  the  way  has  been 
prepared  for  a  successful  fight  against  trypano- 
some diseases.  At  the  same  time  we  are  also 
justified  in  hoping  that  even  beyond  these 
narrow  limits  the  studies  may  prove  generally 
fruitful  in  the  great  campaign  against  infectious 
diseases, 


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